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Polygenic indicators of intercourse variations in choice in people from the UK Biobank


Quotation: Ruzicka F, Holman L, Connallon T (2022) Polygenic indicators of intercourse variations in choice in people from the UK Biobank. PLoS Biol 20(9):
e3001768.

https://doi.org/10.1371/journal.pbio.3001768

Tutorial Editor: Nick H. Barton, Institute of Science and Expertise Austria (IST Austria), AUSTRIA

Acquired: September 30, 2021; Accepted: July 27, 2022; Printed: September 6, 2022

Copyright: © 2022 Ruzicka et al. That is an open entry article distributed beneath the phrases of the Artistic Commons Attribution License, which allows unrestricted use, distribution, and copy in any medium, supplied the unique creator and supply are credited.

Knowledge Availability: All related code is out there on the next public github repositories (/filipluca/polygenic_SA_selection_in_the_UK_biobank/ and /lukeholman/UKBB_LDSC/) and all related knowledge is out there throughout the manuscript, Supporting Info recordsdata, and at https://zenodo.org/document/6824671.

Funding: This work was supported by an Australian Analysis Council Discovery Undertaking Grant FT170100328, to TC. (www.arc.gov.au) The funders had no position in examine design, knowledge assortment and evaluation, choice to publish, or preparation of the manuscript.

Competing pursuits: The authors have declared that no competing pursuits exist.

Abbreviations:
FDR,
false discovery price; GWAS,
genome-wide affiliation examine; LD,
linkage disequilibrium; LRS,
lifetime reproductive success; NCD,
non-central deviation; SA,
sexually antagonistic; SC,
sexually concordant; SHBG,
intercourse hormone binding globulin; SNP,
single-nucleotide polymorphism

Introduction

Adaptation of a inhabitants to its surroundings requires heritable genetic variation for health [1]. Though many populations present substantial genetic variation for health elements [2]—together with life historical past traits corresponding to maturation price, lifespan, mating success, and fertility [2,3]—genetic trade-offs between elements or between several types of people in a inhabitants, restrict adaptive potential [4]. For instance, a mutation that will increase the likelihood of survival to maturity may concurrently lower grownup reproductive success (e.g., [5]), weakening the mutation’s web health impact [4]. Along with slowing adaptation [68], genetic trade-offs can enhance standing genetic variation [2,9], give rise to balancing choice [10,11], and favour evolutionary transitions between mating methods [12,13], modes of intercourse willpower [14], and genome buildings [1518].

Sexually antagonistic (SA) genetic polymorphisms—by which the alleles that profit one intercourse are dangerous to the opposite—are a sort of genetic trade-off which may be widespread in sexually reproducing species [19]. Concept reveals that SA polymorphisms are more likely to come up when mutations differentially have an effect on trait expression in every intercourse or when mutations equally have an effect on traits beneath divergent directional choice between the sexes [20]. Empirical quantitative genetic research indicate that each situations are continuously met in nature [2124] and, accordingly, that SA polymorphisms contribute to phenotypic variation in a spread of plant and animal populations (e.g., [2527]), together with people [2831].

Though there may be now plentiful proof that SA polymorphisms contribute to phenotypic variation, efforts to determine and characterise SA alleles in genomic knowledge face 2 formidable challenges [32]. First, strategies utilizing express health measurements to determine SA polymorphisms (e.g., genome-wide affiliation research (GWAS) of health [33]) are hardly ever possible, as a result of it’s difficult to acquire health measurements for giant numbers of genotyped people beneath pure situations [2]. Second, strategies utilizing allele frequency variations between grownup females and males as genomic indicators of SA viability choice (e.g., between-sex FST estimates [32,3443]) are restricted in a number of methods: They’ve low energy to detect SA loci, they can not distinguish SA choice from intercourse variations within the energy of choice, they’re prone to artefacts generated by inhabitants construction and mis-mapping of sequence reads to intercourse chromosomes [32,40,41,44], they usually neglect health elements apart from viability, corresponding to reproductive success [32,45]. Earlier research of human genomic knowledge [32,3436,43,44,46] have been affected by a number of of those points, such that we at the moment lack strong proof of SA genomic variation in people. Extra usually, these impediments assist to elucidate the restricted catalogue of SA polymorphisms throughout species [4749], which at the moment includes a handful of loci with exceptionally massive phenotypic results (e.g., [5054]).

Regardless of these challenges, new datasets and analytical approaches present alternatives to determine strong genomic indicators of SA choice. First, large “biobank” datasets, that are extensively utilized in human genomics, typically embody each genotype and offspring quantity knowledge [29,55] that can be utilized to detect loci with SA results on reproductive elements of health [32]. Second, estimates of allele frequency variations between sexes—although ill-suited for confidently figuring out particular person SA loci affecting viability—might nonetheless be amenable to genome-wide checks for polygenic SA viability choice [32,34]. Third, inhabitants genomic metrics of sex-differential choice (e.g., between-sex FST) might embody an considerable proportion of real SA loci within the higher tails of their distributions, offering a set of candidate loci that may collectively yield insights into the final properties of SA polymorphisms (e.g., their practical traits and evolutionary dynamics), regardless of uncertainty about particular person candidates.

Right here, we lengthen [32,34] and develop new statistical checks based mostly on FST metrics of between-sex allele frequency differentiation to detect polygenic indicators of sex-differential choice affecting viability, copy, and complete health throughout a full generational cycle. Making use of these checks to the UK Biobank [55]—a dataset comprising quality-filtered genotype and offspring quantity knowledge for about 250,000 women and men—reveals polygenic indicators of sex-differential and SA polymorphism. We corroborate these outcomes through the use of mixed-model statistics that explicitly management for systematic variations within the genetic ancestry of feminine and male people. We minimise potential sequencing artefacts and additional present that sex-differentiated polymorphisms are preferentially located in practical, phenotype-altering genomic sequences. Lastly, we use genetic variety knowledge to look at modes of evolution affecting sex-differentiated websites.

Outcomes

Genomic indicators of intercourse variations in choice: Theoretical predictions

Earlier research have examined sex-differential results of genetic variation through the zygote-to-adult stage by evaluating allele frequencies between grownup females and males [32,34,3640,44]. Against this, our analytical method combines allele frequency with offspring quantity knowledge to estimate sex-differential results throughout a full generational life cycle (Fig 1). As an example the method, think about a big, well-mixed inhabitants containing many polymorphic, biallelic, autosomal loci. At fertilisation, mendelian inheritance equalises allele frequencies between the sexes (Fig 1, left field). Within the zygote-to-adult stage, loci with sex-differential results on survival accumulate allele frequency variations between the adults of every intercourse (e.g., the black allele turns into enriched in grownup males and poor in grownup females as a result of it improves zygote-to-adult survival in males however reduces it in females; Fig 1, center field). Among the many adults, alleles with sex-differential results on reproductive success have totally different transmission charges to the following technology from surviving females versus surviving males (e.g., the black allele is enriched among the many male gametes contributing to fertilisation however poor amongst feminine gametes, thus growing its transmission to offspring of males however reducing transmission to offspring of females; Fig 1, proper field).

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Fig 1. Partitioning indicators of intercourse variations in choice amongst health elements.

A pair of autosomal alleles are represented by white and black dots, representing female- and male-beneficial alleles, respectively; , and depict sex-specific frequency estimates for a given allele at totally different phases of the life cycle (see essential textual content for particulars). Autosomal allele frequencies are equalised between sexes at fertilisation (left field; females, high; males, backside), leading to negligible allele frequency differentiation at this stage of the life cycle. Differentiation between sexes can come up within the pattern of adults (center field) as a consequence of intercourse variations in viability choice amongst juveniles (orange arrow) and within the projected gametes (proper field) as a consequence of intercourse variations in LRS amongst adults (inexperienced arrow). Knowledge on sex-specific allele frequencies and LRS thus enable the estimation of sex-differential results of genetic variants on every health part (together with total health; purple arrow), regardless of the absence of allele frequency knowledge amongst zygotes (left field) and gametes (proper field), that are inferred and never instantly noticed. LRS, lifetime reproductive success.


https://doi.org/10.1371/journal.pbio.3001768.g001

Grownup allele frequencies, coupled with offspring quantity knowledge per particular person, thus present a possibility to estimate sex-differential results of genetic variation throughout an entire life cycle, despite the fact that zygotic and gametic allele frequencies are inferred and never instantly noticed. Under, we apply our method to the UK Biobank, a dataset that features genotypes and reported offspring numbers (hereafter “lifetime reproductive success” or LRS, following commonplace terminology [29]) amongst putatively post-reproductive adults (ages 45 to 69 after filtering; see Supplies and strategies). For a biallelic autosomal locus with alleles A1 and A2, we denote and the respective estimated frequencies of the A1 allele in grownup men and women of the UK Biobank. The projected frequencies of A1 in paternal and maternal gametes contributing to fertilisation are:
(1A)
(1B)
the place Mij and Fij signify the cumulative LRS of men and women, respectively, with genotype ij (e.g., M11, M12, and M22 correspond to genotypes A1A1, A1A2, and A2A2).

Utilizing FST [56], we partition between-sex allele frequency differentiation over 1 technology into 3 elements: (i) differentiation amongst adults, which incorporates results of sex-differential survival (hereafter “grownup FST;” see [32,34,45]); (ii) sex-differential variation in grownup LRS (hereafter “reproductive FST”); and (iii) sex-differential variation in total health (hereafter “gametic FST”). Single-locus estimates of grownup, reproductive, and gametic FST are outlined, respectively, as:
(2A)
(2B)
(2C)
the place and .

FST distributions within the absence of sex-differential choice

Within the absence of intercourse variations in choice (e.g., beneath neutrality or beneath sexually concordant (SC) collection of equal magnitude and path in every intercourse), with massive pattern sizes, negligible Hardy–Weinberg deviations at delivery, and excluding single-nucleotide polymorphisms (SNPs) with very low minor allele frequencies, we present that the grownup, reproductive, and gametic metrics converge, respectively, to the next distributions:
(3A)
(3B)
(3C)
the place every X is an impartial chi-square random variable with 1 diploma of freedom, Nf and Nm denote grownup pattern sizes, μf and μm denote imply LRS, and denote variances in LRS, and and quantify sex-specific departures from Hardy–Weinberg equilibrium within the pattern of adults (Part A in
S1 Appendix). In datasets such because the UK Biobank, there may be additionally between-site variation within the variety of genotyped people and the extent of Hardy–Weinberg deviations within the grownup pattern. The null distributions described by Eqs [3A3C] are simply adjusted to account for this between-site variation (see Supplies and strategies).

Relative to the null distributions in Eqs [3A3C], intercourse variations in choice inflate every metric (Part A in S1 Appendix). These inflations might come up as a consequence of polymorphisms beneath sex-differential choice and impartial polymorphisms that hitchhike with chosen polymorphisms. Nevertheless, linkage disequilibrium (LD) alone can not inflate genome-wide within the absence of real chosen polymorphisms (Part B in S1 Appendix). As such, inflations signify dependable indicators of sex-differentially chosen polymorphism [32], supplied: (i) technical artefacts are managed (as proven under); (ii) sex-specific inhabitants construction is managed; and (iii) men and women are sampled at random (although (iii) will not be a requirement for reproductive ; see Dialogue). To simplify the presentation, we first current analyses utilizing FST metrics, however we return to non-FST metrics within the part titled “Controlling for sex-specific inhabitants construction.”

Genomic indicators of intercourse variations in choice: Empirical knowledge

UK Biobank SNP knowledge.

The pattern measurement within the UK Biobank, after eradicating people that had been intently associated, had a recorded ancestry apart from “White British,” or had lacking LRS knowledge, was N = 249,021 (Nm = 115,531 males and Nf = 133,490 females). We eliminated uncommon polymorphic websites (MAF < 1%), websites with low genotype or imputation high quality, and websites with excessive potential for artefactual between-sex differentiation based mostly on standards recognized by Kasimatis and colleagues [44] (i.e., between-sex variations in lacking charges, deficits of minor allele homozygotes, and heterozygosity ranges exceeding what could be plausibly be defined by intercourse variations in choice; see Part C in S1 Appendix). Reassuringly, not one of the 8 websites that Kasimatis and colleagues [44] recognized as false positives for sex-differential viability choice seem among the many quality-filtered, LD-pruned, imputed SNPs (N = 1,051,949) which might be the main focus of our analyses.

Noticed FST distributions relative to null distributions

We examined for intercourse variations in choice by calculating grownup, reproductive, and gametic (Eqs [2A2C]) within the UK Biobank and contrasting these estimates in opposition to: (i) their respective theoretical null distributions (Eqs [3A3C]); and (ii) empirical null distributions (generated by a single random permutation of female and male labels amongst people or, within the case of reproductive , a single permutation of LRS amongst people of every intercourse; see Supplies and strategies).

All 3 metrics confirmed higher between-sex differentiation than predicted by their theoretical and empirical null distributions, in keeping with intercourse variations in choice with respect to mortality, LRS, and complete health. Imply grownup within the noticed knowledge was bigger than predicted by each null distributions (theoretical null: 2.039 × 10−6; permuted null: 2.043 × 10−6; noticed: 2.104 × 10−6; Wilcoxon and Kolmogorov–Smirnov checks, p < 0.001; Fig 2A and 2D), with a 14.1% and 13.7% extra of SNPs within the high percentile of the theoretical and empirical nulls, respectively (χ2 checks, p < 0.001). Imply reproductive was additionally bigger than predicted by each nulls (theoretical null: 8.731 × 10−7; permuted null: 8.749 × 10−7; noticed: 8.900 × 10−7; Wilcoxon and Kolmogorov–Smirnov checks, p < 0.001; Fig 2B and 2E), with a 7.4% and 5.0% extra of SNPs within the high percentile of the theoretical and empirical nulls ( checks, p < 0.001). Furthermore, imply gametic was bigger than predicted by each nulls (theoretical null: 2.908 × 10−6; permuted null: 2.907 × 10−6; noticed: 2.974 × 10−6; Wilcoxon and Kolmogorov–Smirnov checks, p < 0.001; Fig 2C and 2F), with a 9.0% and seven.8% extra of SNPs within the high percentile of the theoretical and empirical nulls (χ2 checks, p < 0.001).

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Fig 2.

Polygenic indicators of sex-differential choice: Inflation in metrics relative to their nulls. (A–C) Proportion of websites (colored, noticed; gray, permuted) falling into every of 100 quantiles of the theoretical null distributions of grownup (A), reproductive (B), and gametic (C). Theoretical null knowledge (x-axes) had been generated by simulating values (nSNPs = 1,051,949) from a chi-square distribution with 1 diploma of freedom. For every locus, noticed and permuted values had been scaled by the multiplier of the related theoretical null distributions (i.e., the multiplier in Eqs [3A3C] for grownup, reproductive, and gametic , respectively; see Supplies and strategies). Within the absence of intercourse variations in choice, roughly 1% of noticed SNPs ought to fall into every quantile of the null (dashed line). LOESS curves (±SE) are introduced for visible emphasis. (D–F) Distinction between the imply of noticed and empirical null knowledge for every metric (i.e., grownup, reproductive, and gametic , respectively) (high), and the distinction between noticed and theoretical null knowledge (backside), throughout 1,000 bootstrap replicates. Vertical line intersects zero (no distinction between noticed and null knowledge). As in panels (A–C), values had been scaled by the related theoretical null distributions. The code and knowledge wanted to generate this determine could be discovered at https://github.com/filipluca/polygenic_SA_selection_in_the_UK_biobank and https://zenodo.org/document/6824671. SNP, single-nucleotide polymorphism.


https://doi.org/10.1371/journal.pbio.3001768.g002

Indicators of intercourse variations in choice in grownup, reproductive, and gametic had been polygenic. For instance, genetic variants located in genomic areas with excessive LD tended to elucidate extra SNP heritability of every metric than variants located in low-LD areas, as predicted if every sex-differential health part has a polygenic foundation (Part D in S1 Appendix). Furthermore, no particular person locus had a p-value under the Bonferroni-corrected threshold of 4.753 × 10−8, implying that the numerous total inflations weren’t pushed by a small variety of strongly sex-differentiated polymorphisms (grownup : minimal p- and q-values = 2.237 × 10−7 and 0.176; reproductive : minimal p- and q-values = 3.925 × 10−7 and 0.413; gametic : minimal p- and q-values = 4.152 × 10−6 and 0.821).

Types of sex-differential choice: Theoretical predictions

The elevations reported above point out the presence of polygenic sex-differential choice within the UK Biobank. Nevertheless, the indicators might have arisen due to SA choice, due to intercourse variations within the energy however not the path of choice (i.e., sex-differential SC choice), or a mixture of each eventualities. To partition indicators affecting LRS into SA and SC elements, we examined the consequences of a given allele on LRS in every intercourse relative to the opposite. Particularly, estimates of the product ought to are typically adverse when alleles have SA results and optimistic when alleles have SC results (Fig 3A). A brand new metric, termed “unfolded reproductive , ” offers a standardised measure of the product of sex-specific results on LRS:
(4)

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Fig 3. Partitioning indicators of sex-differential choice into SA and SC elements reveals their joint contributions.

(A) As in Fig 1, , and depict sex-specific frequency estimates for a given allele at totally different phases of the life cycle. Underneath SA choice (high), the white allele is female-beneficial and the black allele is male-beneficial, which tends to generate adverse values of unfolded reproductive . Underneath SC choice (backside), the black allele is useful in each sexes, which tends to generate optimistic values of unfolded reproductive . (B) Proportion of websites (turquoise: noticed; gray: permuted) falling into every of 100 quantiles of the theoretical null distributions of unfolded reproductive . Theoretical null knowledge (x-axes) had been generated by simulating values (nSNPs = 1,051,949) from the null (i.e., the product of two commonplace regular distributions). Within the absence of sex-differential choice, roughly 1% of noticed SNPs ought to fall into every quantile of the null (dashed line). LOESS curves (±SE) are introduced for visible emphasis. (C) Distinction, for unfolded reproductive , between the imply noticed and empirical null knowledge (high) and between noticed and theoretical null knowledge (backside), throughout 1,000 bootstrap replicates. The vertical line intersects zero, indicating no distinction between the noticed and null knowledge. Variations between noticed and null knowledge had been obtained individually for adverse and optimistic values of unfolded reproductive . This illustrates that there’s enrichment of SNPs in each tails of the null. The code and knowledge wanted to generate this determine could be discovered at https://github.com/filipluca/polygenic_SA_selection_in_the_UK_biobank and https://zenodo.org/document/6824671. SA, sexually antagonistic; SC, sexually concordant; SNP, single-nucleotide polymorphism.


https://doi.org/10.1371/journal.pbio.3001768.g003

Within the absence of any choice on LRS, unfolded reproductive is distributed because the product of two impartial, commonplace regular distributions (i.e., symmetrically distributed with a imply of zero; see Part E in S1 Appendix). SA choice generates an extra of loci within the decrease quantiles of this null mannequin, whereas SC choice generates an extra of loci within the higher quantiles of the null. Notice that intercourse variations in SC choice should not required to generate an extra of optimistic values for unfolded reproductive (SC collection of equal magnitude within the sexes can generate it as nicely), however SA choice is required to generate an extra of adverse values.

Controlling for sex-specific inhabitants construction

In precept, polygenic elevations can come up totally within the absence of real intercourse variations in choice if there are systematic variations in ancestry (inhabitants construction) between sexes within the sampled inhabitants [32,45]. We due to this fact replicated our analyses utilizing mixed-model affiliation checks which might be analogous to however which explicitly right for sex-specific inhabitants construction (see additionally Part F in S1 Appendix).

We first re-evaluated indicators of intercourse variations in viability choice current in grownup by performing a GWAS of intercourse [32,43,44] utilizing standardised estimates of the log-odds ratio (; see Supplies and strategies). Like grownup quantifies between-sex allele frequency variations amongst adults; furthermore, it controls for inhabitants construction by together with a kinship matrix of genome-wide relatedness between people and principal elements that seize structure-induced axes of genetic variation (see Supplies and strategies). As anticipated, was extremely correlated with grownup (rg ± SE = 1.046 ± 0.020; p < 0.001), and imply was elevated relative to its empirical null distribution (null : 5.236 × 10−7; noticed: 5.323 × 10−7; Wilcoxon and Kolmogorov–Smirnov checks, p < 0.001; Fig 4A and 4D), with 8.9% extra of SNPs within the high percentile of the empirical null (χ2 check, p < 0.001).

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Fig 4.

Construction-corrected metrics reaffirm -based indicators of sex-differential choice. (A–C) Proportion of websites falling into every of 100 quantiles of the empirical null distributions of , |t|, and unfolded t. Within the absence of intercourse variations in choice, roughly 1% of noticed SNPs ought to fall into every quantile of the null (dashed line). LOESS curves (±SE) are introduced for visible emphasis. (D–F) Distinction between the imply of every metric in noticed and empirical null knowledge throughout 1,000 bootstrap replicates. Vertical line intersects zero (no distinction between noticed and null knowledge). For unfolded t, variations between noticed and null knowledge had been obtained individually for adverse and optimistic values. This illustrates that there’s enrichment of SNPs in each tails of the null. The code and knowledge wanted to generate this determine could be discovered at https://github.com/filipluca/polygenic_SA_selection_in_the_UK_biobank and https://zenodo.org/document/6824671. SNP, single-nucleotide polymorphism.


https://doi.org/10.1371/journal.pbio.3001768.g004

We then re-evaluated indicators of sex-differential choice by means of reproductive success by performing separate GWAS for LRS in females and males, every corrected for inhabitants construction, and quantifying the distinction between feminine and male impact sizes utilizing a t-statistic (|t|; see Supplies and strategies). As anticipated, |t| was extremely correlated with reproductive (rg ± SE = 1.025 ± 0.059, p < 0.001) and imply |t| was elevated relative to its empirical null (null = 0.796, noticed = 0.811, Wilcoxon and Kolmogorov–Smirnov checks, p < 0.001; Fig 4B and 4E), with an 11.9% extra of SNPs within the high percentile of the empirical null (χ2 check, p < 0.001).

We additionally developed an analogue of unfolded reproductive , termed unfolded t (see Supplies and strategies), to partition indicators of sex-differential reproductive choice into SA and SC elements. As with unfolded reproductive , SC choice ought to generate an enrichment of values within the higher quantiles of its null, whereas SA choice ought to generate an enrichment of values in its decrease quantiles; in contrast to unfolded reproductive , this metric additionally controls for inhabitants construction. Corroborating earlier outcomes, we noticed an extra of excessive values of unfolded t (imply t amongst websites with t > 0; permuted null = 0.639, noticed = 0.692, Wilcoxon and Kolmogorov–Smirnov checks, p < 0.001; Fig 4C and 4F) and an extra of low values of unfolded t (imply t amongst websites with t < 0; permuted null = –0.639, noticed = –0.649, Wilcoxon and Kolmogorov–Smirnov checks, p < 0.001), signalling the presence of SC and SA polymorphisms, respectively.

Lastly, we examined genetic correlations between metrics. These analyses confirmed that metrics of sex-differential LRS choice weren’t considerably correlated with metrics of sex-differential mortality choice throughout loci (Fig 5A). For instance, the genetic correlation (estimated by way of LD rating regression) between grownup and reproductive was –0.24 (SE = 0.16, p = 0.13) and the genetic correlation between and |t| was –0.16 (SE = 0.16, p = 0.31).

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Fig 5. Indications that sex-differentiated loci usually tend to be practical and contribute to trait variation.

(A) Genetic correlations between metrics of sex-differential choice. Optimistic correlations (orange) indicate that alleles have comparable sex-specific results on given health elements, whereas adverse correlations (purple) indicate that alleles have opposing sex-specific results on given health elements; * denotes unadjusted p < 0.05. (B) Enrichments (±SE) of sex-differentiated loci in main practical classes. For every metric, enrichments had been calculated because the relative SNP heritability (as a fraction of complete SNP heritability) defined by a given practical class, divided by the relative variety of SNPs (as a fraction of all SNPs) current in a given practical class. Dashed line = 1 (no enrichment). “Unfavorable” and “Optimistic” discuss with adverse and optimistic values (i.e., SA and SC elements, respectively) of unfolded reproductive and unfolded t metrics. (C) Genetic correlations between metrics of sex-differential choice and numerous UK Biobank phenotypes (as analysed by the Neale laboratory). Metrics of sex-differential choice have been polarised, such that optimistic correlations (purple) counsel that greater trait values are extra helpful to females than males (for the related health part), whereas adverse correlations (blue) counsel that greater trait values are extra helpful to males than females (see Dialogue for caveats surrounding this interpretation); ** denotes FDR-adjusted p < 0.05 and * denotes unadjusted p < 0.05. The code wanted to generate this determine could be discovered at https://github.com/filipluca/polygenic_SA_selection_in_the_UK_biobank and https://github.com/lukeholman/UKBB_LDSC, with knowledge at https://zenodo.org/document/6824671. FDR, false discovery price; SA, sexually antagonistic; SC, sexually concordant; SNP, single-nucleotide polymorphism.


https://doi.org/10.1371/journal.pbio.3001768.g005

Practical and phenotypic results of sex-differentiated loci

If sex-differentiated loci replicate real sex-differential choice—reasonably than random probability, genotyping errors, or inhabitants construction—such polymorphisms ought to be preferentially present in functionally vital areas within the genome. We due to this fact performed enrichment checks, each to assist our inference that sex-differential choice is going on and to discover practical results of sex-differentiated loci.

We first used LD rating regression [57] to check whether or not websites with excessive sex-differentiation are typically present in main practical classes within the genome (coding, 3′UTR and 5′UTR areas). If a given class is enriched for real chosen SNPs, the anticipated heritability tagged by these SNPs (i.e., what LD rating regression measures) ought to exceed the fraction of SNPs current in that practical class. Whereas practical enrichment estimates had been noisy and thus not statistically distinguishable from 1 (no enrichment) after multiple-testing correction (Fig 5B), every estimate persistently exceeded 1 throughout practical classes and metrics, suggesting that sex-differentiated loci usually tend to have phenotype-altering results than anticipated by probability.

Additional proof for the phenotype-altering results of sex-differentiated loci was sought by means of direct comparisons between metrics of sex-differential choice and the Neale laboratory database of UK Biobank GWAS. Particularly, we used cross-trait LD rating regression [58] to estimate genetic correlations between metrics of sex-differential choice and 30 phenotypes, chosen for his or her medical relevance and/or relationship to phenotypic intercourse variations. Although many important associations didn’t survive a number of testing correction (Fig 5C), a number of disease-relevant and quantitative traits (age at menarche, physique fats proportion, ailments of the attention and adnexa, fluid intelligence, harm, neuroticism rating, SHBG [sex hormone binding globulin], standing top) signify candidates for sex-differential viability and LRS choice, whereas different traits (testosterone, hypertension) signify candidates for sex-differential viability choice.

Modes of evolution of sex-differentiated loci: Theoretical predictions

To realize perception into the modes of evolution affecting sex-differentiated websites, we investigated the affiliation between metrics of sex-differential choice and MAF within the UK Biobank. Within the absence of any modern intercourse variations in choice, all between-sex metrics ought to be impartial of MAF (Part G in S1 Appendix). Within the presence of sex-differential choice, the affiliation between every metric and MAF can doubtlessly be optimistic or adverse, relying on the patterns of up to date and historic choice affecting loci all through the genome. A optimistic covariance between and MAF ought to come up when alleles topic to sex-differential choice usually segregate at intermediate frequencies, as might happen beneath a historical past of balancing choice or drift (Part G in S1 Appendix) or non-equilibrium eventualities corresponding to incomplete selective sweeps. In distinction, a adverse affiliation between MAF and between-sex is predicted for loci which have advanced beneath sex-differential purifying choice (Part G in S1 Appendix). This adverse covariance arises as a result of purifying choice disproportionately lowers the frequency of large-effect alleles (these producing bigger values) relative to small-effect alleles [59]. Briefly, optimistic associations with MAF point out that purifying choice will not be the dominant mode of evolution affecting loci beneath sex-differential choice and as a substitute sign a current historical past of balancing choice, optimistic choice, or drift.

Whereas associations between metrics of sex-differential choice and MAF present insights into comparatively current and modern patterns of choice affecting sex-differentiated websites, they don’t present insights into their deeper evolutionary histories. To look at this, we examined the particular speculation that sex-differentiated websites are topic to long-term balancing choice, as predicted for SA polymorphisms beneath sure eventualities of choice and dominance [10]. Underneath long-term balancing choice, we’d count on sex-differentiated (and linked) loci to be previous, to exhibit low between-population , to exhibit excessive genetic variety, and to disproportionately co-localise with earlier candidates for long-term balancing choice, in comparison with much less sex-differentiated websites with comparable allele frequencies within the UK Biobank.

Modes of evolution of sex-differentiated loci: Empirical knowledge

Inspecting the connection between MAF and metrics of sex-differential choice within the UK Biobank knowledge revealed persistently optimistic correlations (grownup = 0.009, p < 0.001; : ρ = 0.006, p = 0.216; reproductive , ρ = 0.006, p < 0.001; |t|: ρ = 0.005, p < 0.001; gametic , ρ = 0.007, p < 0.001; Fig 6A–6D), with all correlations stronger in noticed than null knowledge (Part H in S1 Appendix). Given the absence of adverse correlations between MAF and every metric, we are able to reject purifying choice because the dominant mode of evolution affecting sex-differentiated websites. The optimistic correlations as a substitute counsel that balancing choice, drift, or incomplete selective sweeps characterise the evolution of sex-differentiated loci.

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Fig 6. Modes of evolution of sex-differentiated websites.

(A–D) Imply MAF, within the UK Biobank, throughout 100 quantiles of the null for every metric of sex-differential choice. For metrics, x-axes correspond to Fig 2A–2C (and Fig 3B for unfolded reproductive ). For mixed-model metrics, x-axes correspond to Fig 4A–4C. LOESS curves (±SE) are introduced for visible emphasis. (E-H) Imply age of the choice (i.e., non-reference) allele throughout 100 quantiles of the null for every metric of sex-differential choice. Every panel corrects for ascertainment bias of allele frequencies amongst extremely sex-differentiated websites (i.e., Fig 6A–6D). For visualization functions, this was completed by averaging, in every quantile, allele age throughout 20 quantiles of different allele frequency within the UK Biobank (such that UK Biobank different allele frequency is roughly equal throughout quantiles). LOESS curves (±SE) are introduced for visible emphasis. The code and knowledge wanted to generate this determine could be discovered at https://github.com/filipluca/polygenic_SA_selection_in_the_UK_biobank and https://zenodo.org/document/6824671.


https://doi.org/10.1371/journal.pbio.3001768.g006

We then examined the speculation that long-term balancing choice has formed the evolutionary histories of sex-differentiated loci. We centered our analyses on 4 measures of balancing choice: allele age estimates from the Atlas of Variant Age database [60], between-population and Tajima’s D estimates from 2 non-European populations from the 1000 Genomes Undertaking [61], and three units of candidate loci for long-term balancing choice [6264]. In every case, we seemed for associations between metrics of sex-differential choice and balancing choice, whereas controlling for ascertainment bias of intermediate-frequency alleles (that are, on common, older and thus extra more likely to be beneath long-term balancing choice regardless of the energy of sex-differential choice) amongst extremely sex-differentiated websites (see Supplies and strategies). General, we discovered little assist for the speculation of long-term balancing choice affecting sex-differentiated loci. After corrections for a number of testing throughout metrics of sex-differential choice (see Part I in S1 Appendix, for full statistical outcomes), we discovered weak or absent associations with allele age (Fig 6E–6H), between-population (Part I in S1 Appendix), genetic variety (Part I in S1 Appendix), or earlier candidates for balancing choice (Part I in S1 Appendix). We discovered some indications that candidate SA alleles (i.e., loci with adverse values of unfolded reproductive and unfolded t) had been older than the genome-wide common (Fig 6H), and loci experiencing robust SC choice (i.e., optimistic values of unfolded reproductive and unfolded t) had been youthful (Fig 6H).

Dialogue

Intercourse variations in directional choice on phenotypes have been reported in a variety of animal taxa [19,2123,65], together with post-industrial human populations [2830], but inhabitants genomic indicators of sex-differential choice—not to mention SA choice—have been extraordinarily tough to ascertain. The reason being easy: Sexual copy equalises autosomal allele frequencies between the sexes each technology, limiting genetic divergence and, in impact, stopping using widespread checks to deduce intercourse variations in choice (e.g., McDonald–Kreitman checks for optimistic choice, FST outlier checks for spatially various choice [6668]). Printed research utilizing human genomic knowledge illustrate the challenges of finding out polymorphisms with sex-differential health results [32,45], together with pattern sizes which may be inadequate for detecting polygenic indicators of sex-differential choice, lack of controls for inhabitants construction or technical artefacts, and/or absence of knowledge regarding reproductive health elements.

Indicators of sex-differential choice within the UK Biobank

We developed a theoretical framework for finding out genomic variation with sex-differential results throughout an entire life cycle. Our method extends present work based mostly on between-sex allele frequency differentiation amongst adults—a possible sign of sex-differential viability choice amongst juveniles [32,34,45]—to additional embody reproductive success elements and complete health. Making use of this method to knowledge from a quarter-million UK adults, we current proof for polygenic indicators of sex-differential choice in people. Particularly, UK Biobank people confirmed intercourse variations in allele frequencies—each amongst adults and their (projected) offspring—that persistently exceeded expectations outlined by our theoretical null fashions for viability, reproductive, and complete health and endured after controlling for potential artefacts arising from mis-mapping of reads to intercourse chromosomes [44].

Though we focussed on FST as our metric of differentiation for quite a lot of causes (its simplicity, amenability to theoretical modelling, and wealthy historical past in inhabitants genetic research of adaptation [6668]), an vital downside of FST is its lack of ability to manage for systematic intercourse variations within the genetic ancestry of sampled people. We due to this fact used FST analogues based mostly on mixed-model affiliation checks to manage for sex-specific inhabitants construction. These FST analogues corroborated FST-derived indicators of sex-differential choice on every part, with clear enrichments within the higher tails of every null distribution. Extra assist for real sex-differential choice got here from practical enrichment analyses, which, regardless of noisy particular person estimates, persistently indicated that sex-differentiated websites had been located in practical genomic areas and contributed to variation for a lot of phenotypes.

An vital limitation of metrics of sex-differential choice affecting non-LRS health elements (i.e., grownup FST, gametic FST, and their mixed-model analogues) utilized to the UK Biobank is that UK Biobank people are sampled by means of energetic participation. Consequently, as famous by Pirastu and colleagues [43], intercourse variations within the genetic foundation of people’ predisposition to participate within the UK Biobank might generate intercourse variations in grownup allele frequencies. To assist this argument, Pirastu and colleagues [43] reported considerably higher SNP heritability of intercourse (a polygenic measure of intercourse variations in allele frequencies) in biobanks counting on energetic participation than in biobanks utilizing passive participation. Nevertheless, their evaluation is inconclusive as a result of the passive participation research they analysed had been smaller (NBiobank Japan = 178,242, NFinnGen = 150,831, NiPsych = 65,891) than energetic participation research (NUK Biobank = 452,302, N23andme = 2,462,132). Thus, variations in statistical energy between research (and/or variations within the extent of sex-differential viability choice between populations) might account for his or her outcomes. Furthermore, the optimistic level estimates of SNP heritability for passive participation research counsel that substantial allele frequency variations between the sexes are attainable. For instance, mortality after fertilisation, however earlier than delivery, could be very excessive in people (on the order of fifty% [69]), giving ample alternative for mortality in formative years to generate allele frequency variations between sexes. In sum, neither their examine nor ours can conclusively distinguish the relative contributions of sex-differential choice and participation bias to allele frequency differentiation between feminine and male adults, although each sources doubtless contribute.

Importantly, participation bias shouldn’t have an effect on metrics of sex-differential choice referring to LRS. Reproductive and its mixed-model analogue, |t|, management for allele frequency variations between samples of adults of every intercourse and rule out elements which may in any other case have an effect on estimated grownup allele frequencies within the UK Biobank (e.g., mis-mapping of reads to intercourse chromosomes, participation biases [43]). Elevations in these metrics thus present essentially the most compelling proof for sex-differential choice within the UK Biobank (see additionally [46]). Furthermore, they’re in keeping with earlier observations in post-industrial human populations, together with variation in feminine and male LRS [70] (a mandatory precondition for sex-differential choice), widespread intercourse variations within the genetic foundation of quantitative traits (e.g., within the UK Biobank [71]), and sex-differential choice on phenotypes (e.g., top [29,30] and multivariate trait mixtures [70]), which ought to collectively result in genome-wide polymorphisms with sex-differential results on health and health elements [20].

Distinguishing between SA and SC types of sex-differential choice

Having established indicators of sex-differential choice affecting LRS, we developed a brand new check for investigating the type of choice—SC or SA—affecting these genomic variants by quantifying the product of a genetic variant’s impact on LRS in every intercourse. Making use of our check to UK Biobank knowledge confirmed that each kinds of variant contribute to indicators of sex-differential choice on LRS, with SC variants contributing comparatively extra enrichment within the higher tail of the null of unfolded reproductive (and its mixed-model analogue, unfolded t) than SA variants contribute within the decrease tail of the null. That indicators of SC polymorphism had been extra pronounced than SA polymorphism is probably unsurprising, given that the majority traits are more likely to be topic to SC reasonably than SA choice [29]. Furthermore, alleles topic to similar SC choice in every intercourse will contribute to the higher tail of unfolded reproductive , however won’t contribute to the decrease tail (or to different metrics of sex-differential choice), which could additionally account for higher obvious sign of SC than SA choice in these analyses. Nonetheless, some human traits have been proven to be beneath SA choice—most notably standing top, which positively covaries with male LRS and negatively covaries with feminine LRS [2830]. The enrichment of websites within the decrease tails of unfolded reproductive and unfolded t is in keeping with these earlier observations. Our discovering that variants that enhance top tended to have male-beneficial and female-detrimental results (i.e., as mirrored by a adverse correlation between top and t) is especially reassuring and validates the instinct that SA choice on the phenotypic degree (e.g., over top) offers rise to SA variation all through the genome.

Modes of evolution affecting sex-differentiated loci

We discovered that sex-differentiated websites had, on common, extra intermediate frequencies than much less sex-differentiated websites. This discovering has a number of implications. First, we count on no affiliation between metrics of sex-differentiation and MAF within the absence of sex-differential choice. Subsequently, these optimistic associations signify an impartial strand of assist for the argument that sex-differential choice is shaping patterns of genome-wide variation within the UK Biobank. Second, the optimistic associations indicate {that a} mannequin of sex-differential purifying choice, by which variants are maintained at mutation-selection-drift steadiness, is insufficient to elucidate enrichments of sex-differentiated websites. Intercourse-differential purifying choice is as a substitute anticipated to generate adverse associations between MAF and the extent of sex-differentiation (a adverse affiliation that’s certainly noticed for a lot of quantitative traits [72]). Lastly, the optimistic associations between sex-differentiation and MAF are in keeping with quite a lot of eventualities, corresponding to current evolutionary histories of balancing choice, genetic drift, or incomplete selective sweeps. Balancing choice or drift can each generate a broad spectrum of allele frequency states at SA loci, by which intermediate-frequency SA variants dominate indicators of sex-differential choice. Alternatively, SC alleles with unequal health results in every intercourse might have lately swept to intermediate frequencies and these variants now dominate indicators of sex-differential choice.

Though optimistic associations between metrics of sex-differential choice and MAF point out that balancing choice could also be current, our analyses didn’t reveal clear indicators of long-term balancing choice amongst sex-differentiated websites. The absence of such indicators might stem from a number of elements. First, SA polymorphisms are solely predicted to expertise balancing choice beneath slim situations [10,73], so SA loci might not expertise balancing choice in any respect. Second, balancing choice might have an effect on sex-differentiated polymorphisms however be too current to generate a transparent statistical sign in our analyses [74]. Third, long-term balancing choice at sex-differentiated loci could also be current however successfully weak, owing to comparatively small Ne in people [75] and the excessive susceptibility of SA alleles to genetic drift [73,76]. Fourth, long-term balancing choice could also be current, however statistical checks for it might be too weak to face out from the background noise of false positives in our metrics and the datasets used to quantify balancing choice [77].

How will we reconcile these outcomes with earlier work in Drosophila melanogaster indicating that candidate SA polymorphisms segregate throughout worldwide populations and even species [33]? A parsimonious rationalization for these contrasting findings is that the effectiveness of balancing choice is decrease in people than fruit flies as a consequence of a lot smaller Ne. Certainly, given the pronounced sensitivity of SA balancing choice to genetic drift [73,76], we must always count on the connection between indicators of SA and balancing choice to range with Ne. Furthermore, earlier work in D. melanogaster focussed on SA polymorphisms [33] to the exclusion of SC polymorphisms, whereas our metrics seize each types of sex-differential variation, thus weakening the facility of checks for associations with indicators of balancing choice. Curiously, once we partitioned indicators of sex-differentiation into SA and SC elements, we discovered indications that candidate SA websites had been certainly older, which suggests that SA balancing choice could also be current however masked by sex-differential SC polymorphisms. General, proof that sex-differentiated, together with SA, polymorphisms contribute to standing genetic variation—as in our examine—is at current a lot stronger than proof that they’re maintained by balancing choice.

Instructions for future analysis

Our analyses counsel various fruitful instructions for additional analysis. First, given the problem of distinguishing participation bias from choice in indicators of between-sex allele frequency differentiation amongst adults, conclusively establishing the presence of sex-differential viability choice in genomic knowledge stays an vital analysis path. Guardian-offspring trio analyses that management for participation results [78], or replication of our evaluation technique in massive datasets sampled by means of passive reasonably than energetic participation, might yield the proof required. Second, the extent to which variants with optimistic results on mortality in a given intercourse have comparable or opposing results on copy bears additional examination. Our discovering that genetic correlations between metrics of viability and reproductive choice weren’t considerably totally different from zero signifies a spread of attainable eventualities. It could counsel that variants affecting every health part are impartial (i.e., as a result of alleles affecting every part are genuinely impartial), that between-sex allele frequency differentiation amongst adults is a poor sign of sex-differential viability choice or {that a} comparable fraction of loci have concordant and antagonistic results, thus additionally producing no web correlation.

Lastly, given the growing availability of genotypic and LRS knowledge, additional work might try to duplicate our evaluation technique in several populations and species. Many taxa exhibit higher variance for reproductive success than people [79], producing greater potential for detecting polygenic indicators of sex-differential choice. In keeping with this, polygenic inflations of grownup have beforehand been documented in modest samples of pipefish and flycatchers [32,38,39], suggesting that intercourse variations in choice is likely to be stronger in these species than in people. Furthermore, these samples are much less prone to ascertainment bias as a result of people don’t actively take part and since sampling can usually be randomised with respect to intercourse. Whereas we count on that polygenic indicators of sex-differential choice will replicate throughout populations of a species (see, for instance, Zhu and colleagues [35]’s replication of the affiliation between testosterone and grownup allele frequency variations in Fig 5C), we warning that there could also be comparatively little overlap when it comes to essentially the most sex-differentiated polymorphisms. One motive is that environmental variations between populations (e.g., cultural variations in household planning between human populations) might alter the set of causal loci beneath sex-differential choice. Another excuse is that the noisiness of polygenic indicators of sex-differential choice [32,45], together with the close to certainty that the majority polymorphic loci have small results on health [80], generates variation within the set of candidate sex-differential polymorphisms recognized throughout populations [81], even when causal sex-differential polymorphisms don’t differ.

Supplies and strategies

High quality management of UK Biobank knowledge

We used sample-level info supplied by the UK Biobank (see [55] for particulars) to carry out individual-level (phenotypic) qc. Particularly, we excluded people with excessive relatedness (third diploma or nearer), non-“white British” ancestry, excessive heterozygosity, and excessive lacking charges. We additionally excluded people whose reported intercourse didn’t match their inferred genetic intercourse, aneuploids, and people with lacking or unreliable LRS knowledge (as detailed under).

We processed LRS knowledge as follows. LRS knowledge had been obtained from UK Biobank subject 2405 “Variety of kids fathered” for males, and subject 2734 “Variety of dwell births” for females. Earlier observations of optimistic genetic correlations between offspring and grand-offspring numbers throughout generations [82] point out that offspring quantity represents a superb proxy for LRS in post-industrial human populations. As a result of some people had been requested to report offspring quantity at repeated evaluation factors, we thought of the utmost offspring quantity reported because the definitive worth of LRS for that particular person. Although misestimation of LRS for every particular person can’t be definitively excluded (e.g., people might misreport and embody non-biological kids, people might reproduce after knowledge assortment), we minimised this risk by eradicating people: (i) youthful than 45 years of age (this cutoff was chosen for consistency with earlier analysis [29] and since Workplace for Nationwide Statistics knowledge signifies that copy could be very restricted for UK people aged 45 and over); (ii) reporting fewer offspring at a later evaluation level than at an earlier evaluation level; (iii) with 20 or extra reported offspring numbers (massive offspring numbers usually led to zero—e.g., 20, 30, 50, 100—and had been thus thought of much less dependable). Moreover, uncounted LRS knowledge add imprecision however shouldn’t systematically bias our analyses.

Along with site-level qc applied by the UK Biobank [55], we used PLINK and PLINK2 [83] to take away imputed websites that had been non-diallelic, had MAF <1%, lacking charges >5%, p-values < 10−6 in checks of Hardy–Weinberg equilibrium, and INFO rating ≤0.8, denoting poor imputation high quality. Whereas these cutoffs prohibit our analyses to a nonrandom subset of all genetic variation, they guard in opposition to sequencing artefacts within the UK Biobank and assist take away websites (e.g., these with MAF <1%) which have little potential to hold statistical sign of sex-differentiation relative to noise induced by sampling error.

Extra artefact filtering in UK Biobank knowledge

Mis-mapping of autosomal reads to intercourse chromosomes can generate between-sex allele frequency variations amongst adults within the absence of intercourse variations in choice [44]. In mild of scant direct proof for SA polymorphisms in people and still-developing bioinformatic strategies for distinguishing artefacts from real sex-differential choice [40,44,8486], our main concern was to cut back the prospect of mapping errors. We did so by excluding: (i) websites with heterozygosity ranges that exceeded what might plausibly be anticipated beneath SA choice (see under and Part C in S1 Appendix); (ii) websites with a deficit of minor allele homozygotes; and (iii) websites exhibiting massive variations in lacking price between sexes. These 3 patterns have beforehand been proven to correlate with mis-mapping of reads to intercourse chromosomes [44]. Whereas these filters cut back the prospect of false positives, in addition they doubtlessly enhance probability of false negatives and due to this fact signify a barely conservative check of sex-differential choice. For instance, the elimination of websites with excessive heterozygosity ranges is predicted to take away websites beneath robust (however not weak or reasonably robust) sex-differential choice; equally, the elimination of websites with massive lacking price variations between sexes might take away real polymorphisms with sex-differential results.

To take away websites with artificially inflated heterozygosity, we estimated FIS for every SNP as:

the place PAa denotes the frequency of heterozygotes for a given locus and the sex-averaged allele frequency. For a SA locus at polymorphic equilibrium, the distribution of is nicely approximated by a traditional distribution with expectation and variance as follows:


the place n is complete pattern measurement of adults, p the minor allele frequency, and smax = max(sm, sf) with sm and sf representing female and male choice coefficients (Part C in
S1 Appendix). To determine SNPs with extra heterozygosity, we in contrast within the noticed knowledge to anticipated beneath robust SA choice (smax = 0.2) by performing a 1-tailed Z-test for extra heterozygosity. We thus obtained p-values for every locus, corrected p-values for a number of testing utilizing Benjamini–Hochberg false discovery charges (FDR) [87], and eliminated websites with FDR q-values under 0.05.

To determine websites with a deficit of minor allele homozygotes, we in contrast the noticed frequency of minor allele homozygotes to the anticipated frequency beneath Hardy–Weinberg equilibrium (p2, the place p is the frequency of the minor allele) by performing a 1-tailed binomial check, eradicating websites with FDR q-values under 0.05. Assessments for extra heterozygosity and deficits of minor allele homozygotes had been carried out throughout all people (no matter intercourse) and likewise for every intercourse individually. Websites had been eliminated in the event that they exhibited q-values under 0.05 in any of the three checks (i.e., each sexes mixed, females, and males). Lastly, to evaluate variations in lacking price between the sexes, we carried out a χ2 check, eradicating websites with FDR q-values under 0.05.

Quantifying polygenic indicators of intercourse variations in choice

Statistical comparisons of null and noticed distributions.

Null distributions for metrics had been theoretically derived (see Sections A and E in S1 Appendix). The theoretical null distributions apply to genome-wide knowledge by which the pattern of feminine and male sequences, imply and variance in LRS, and Hardy–Weinberg deviations, are fixed throughout loci. In apply, there may be variation in pattern sizes, imply LRS, variance in LRS, and the extent of Hardy–Weinberg deviations between loci. To take these elements into consideration, we let the multiplier in Eqs [3A3C] range when it comes to its pattern measurement ( and per diploid locus i), imply and variance in LRS ( and , and and , per diploid locus i) and the extent of Hardy–Weinberg deviations within the pattern ( and per diploid locus i). We then scaled by the multiplier, such that, for every locus:



These scaled estimates, which right for site-specific variation, can then be in comparison with a chi-square distribution with 1 diploma of freedom. For unfolded reproductive , no scaling is required as a result of site-specific changes are already considered within the definition of the metric (Eq [
4]).

Null distributions had been additionally obtained empirically, by means of permutation, as follows. For grownup and gametic , we carried out a single permutation of feminine and male labels and recalculated (scaled by the multiplier, as above) in permuted knowledge. For reproductive and unfolded reproductive , we carried out a single permutation of LRS values inside every intercourse—with out permuting intercourse—and recalculated the statistic (scaled by the multiplier, as above) in permuted knowledge. Permuting LRS with out permuting intercourse is suitable for reproductive and unfolded reproductive as a result of it permits allele frequencies to vary between grownup men and women (as would occur if, for instance, sex-differential viability choice is going on amongst juveniles) however randomises the consequences of genotype on LRS, thus guaranteeing that solely estimation error can contribute to the empirical null. We carried out a single permutation for every metric as a result of performing massive numbers of permutations was computationally unfeasible and since we had been focussed on testing a cumulative sign of choice throughout loci, reasonably than establishing significance on the single-locus degree.

To check for elevations in noticed knowledge relative to the (theoretical or empirical) nulls, we LD-pruned the dataset (settings “—indep-pairwise 50 10 0.2” in PLINK) and ran Wilcoxon rank-sum and Kolmogorov–Smirnov checks. These checks assess variations within the median and distribution of the noticed and null knowledge, respectively. As a complementary approach of evaluating noticed and null knowledge, we quantified enrichment of noticed values within the high 1% of every null utilizing a χ2 check. Lastly, we estimated the distinction between the imply worth of the metric within the noticed knowledge and the imply worth of the metric in every null, acquiring 95% confidence intervals and empirical p-values by means of bootstrapping (1,000 replicates; the place every replicate consists of the set of related SNPs, sampled with substitute).

Controlling for sex-specific inhabitants construction

Case-control GWAS of intercourse.

To enrich the check for sex-differential viability choice based mostly on grownup , we carried out a GWAS of intercourse [32,43,44]. By analogy to grownup , loci with sex-differential results on viability in a GWAS of intercourse will are inclined to have comparatively massive absolute log-odds ratios (comparable to comparatively massive allele frequency variations between sexes). Not like grownup , the GWAS of intercourse method moreover permits the inclusion of covariates that account for inhabitants construction and different attainable confounders [32,43,44].

We used BOLT-LMM to run a mixed-model GWAS [88] utilizing a kinship matrix to account for inhabitants construction. The kinship matrix was constructed from an LD-pruned set of quality-filtered imputed SNPs (LD-pruning settings as above). We added particular person age (subject 54), evaluation centre (subject 21003), and the highest 20 principal elements derived from the kinship matrix, as fixed-effect covariates. To facilitate comparisons with grownup , we standardised the regression coefficients (log-odds ratios) from the GWAS by allele frequency, such that:

the place is the log-odds ratio and is the sex-averaged allele frequency amongst adults. To acquire permuted values, we carried out a single permutation of feminine and male labels and recalculated the statistic within the permuted knowledge.

Features and phenotypic results of sex-differentiated loci

We used stratified LD rating regression [57] to look at whether or not sex-differentiated loci had been extra more likely to be located in putatively practical genomic areas (e.g., coding or regulatory areas) than anticipated by probability. This technique partitions the heritability from GWAS abstract statistics into totally different practical classes, whereas accounting for variations in LD (and thus, elevated tagging of a given causal locus) in several areas of the genome (with LD quantified from European-ancestry samples from the 1000 genome mission, and restricted to SNPs additionally current within the HapMap 3 reference panel [57]). As a result of LD rating regression requires signed abstract statistics as enter, we first reworked our (unsigned) metrics of sex-differential choice to signed metrics (e.g., metrics and had been reworked to Z-scores, |t| was reworked to t), the place optimistic and adverse values denote female- and male-beneficial results of the focal allele, respectively.

Enrichments for 3 putatively practical classes (coding, 3′UTR, 5′UTR) had been then calculated because the fraction of complete heritability defined by a given class divided by the fraction of all SNPs in a given class. Notice that we calculated enrichment for these classes whereas implementing the “full baseline mannequin,” which incorporates 50 additional classes. This mannequin has been proven to offer unbiased enrichments for focal classes [57] and for complete SNP heritability [90] (estimates of complete SNP heritability had been utilized in Part D in S1 Appendix).

We used cross-trait LD rating regression [58] to look at genetic correlations between metrics of sex-differential choice and a collection of phenotypic traits, in addition to between the metrics of sex-differential choice. The tactic calculates genetic correlations between pairs of traits whereas making an allowance for LD-induced variations within the extent of tagging of causal loci throughout the genome. We computed genetic correlations between every metric of sex-differential choice (reworked to a signed statistic, as above, such that greater values of the signed metric usually tend to profit females than males) and an preliminary listing of 43 traits (subsequently filtered to 30 after eradicating traits the place an correct genetic correlation, outlined as SE < 0.2, couldn’t be estimated) [91], and used FDR correction (throughout metrics and traits) on ensuing p-values.

Modes of evolution affecting sex-differentiated loci

Allele ages.

If sex-differentiated variants expertise sufficiently robust and sustained balancing choice relative to the countervailing results of genetic drift, we count on them to be older than the genome-wide common [74]. We used the Atlas of Variant Age database to acquire allele age estimates for genome-wide variants [60]. Estimates of allele age on this database apply to the non-reference (i.e., different) allele and are derived from coalescent modelling of the time to the latest widespread ancestor utilizing the “Genealogical Estimation of Variant Age” technique (see [60] for particulars). Estimates of allele age make use of genomic knowledge from: (i) the 1000 Genomes Undertaking; (ii) the Simons Genome Variety Undertaking; and (iii) each datasets mixed. For every website within the UK Biobank, we obtained the median estimate of allele age from the mixed dataset (when obtainable), from the 1000 Genomes Undertaking, or the Simons Genome Variety Undertaking (when neither different estimate was obtainable).

Between-population FST and Tajima’s D in non-European populations

If candidate SA variants expertise sufficiently robust balancing choice sustaining a set polymorphic equilibrium, they need to exhibit lower-than-average allele frequency variations between populations [74] and larger-than-average allele frequency variety inside populations. We used bcftools [92] to acquire allele frequency knowledge from 2 non-European populations from the 1000 Genomes Undertaking: Yoruba Nigerians (YRI, N = 108) and Gujarati Indians (GIH, N = 103). We then estimated between-population as:

the place and are allele frequency estimates within the related pair of populations and We additionally used vcftools [
93] to calculate Tajima’s D, a metric of genetic variety which takes on elevated values beneath sure evolutionary and demographic eventualities, together with balancing choice, in 10 kb home windows throughout the genome.

Earlier candidates for balancing choice.

If candidate SA variants expertise robust balancing choice, they need to disproportionately co-occur with beforehand recognized candidates for balancing choice. We used 3 impartial units of candidate websites for balancing choice to analyze this risk: (i) the dataset of Andrés and colleagues [62], which consists of 64 genes exhibiting elevated polymorphism (as decided utilizing the Hudson–Kreitman–Aguadé check) and/or intermediate-frequency alleles throughout 19 African-American or 20 European-American people; (ii) the dataset of DeGiorgio and colleagues [64], which consists of 400 candidate genes exhibiting elevated T1 or T2 statistics amongst 9 European (CEU) and 9 African (YRI) people. T1 or T2 statistics quantify the probability {that a} genomic area displays ranges of impartial polymorphism which might be in keeping with a linked balanced polymorphism; (iii) the dataset of Bitarello and colleagues [63], which consists of 1,859 candidate genes exhibiting elevated values of “non-central deviation” (NCD) statistics. NCD statistics additionally quantify the probability that given genomic areas are located close by a balanced polymorphism, utilizing polymorphism knowledge from 50 random people from 2 African (YRI; LWK) and European (GBR; TSI) populations and divergence knowledge from a chimpanzee outgroup.

We assigned every website within the UK Biobank dataset to a gene utilizing SnpEff [94] and categorised websites as candidates or non-candidates for balancing choice based mostly on whether or not they had been annotated as belonging to a candidate or non-candidate gene in every of the three aforementioned datasets.

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