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Evolutionary divergence between homologous X–Y chromosome genes shapes sex-biased biology

Nature Ecology & Evolution volume 9, pages 448–463 (2025)Cite this article

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Abstract

Sex chromosomes are a fundamental aspect of sex-biased biology, but the extent to which homologous X–Y gene pairs (‘the gametologs’) contribute to sex-biased phenotypes remains hotly debated. Although these genes tend to exhibit large sex differences in expression throughout the body (XX females can express both X members, and XY males can express one X and one Y member), there is conflicting evidence regarding the degree of functional divergence between the X and Y members. Here we develop and apply co-expression fingerprint analysis to characterize functional divergence between the X and Y members of 17 gametolog gene pairs across >40 human tissues. Gametolog pairs exhibit functional divergence between the sexes that is driven by divergence between the X versus Y members (assayed in males), and this within-pair divergence is greatest among pairs with evolutionarily distant X and Y members. These patterns reflect that X versus Y gametologs show coordinated patterns of asymmetric coupling with large sets of autosomal genes, which are enriched for functional pathways and gene sets implicated in sex-biased biology and disease. Our findings suggest that the X versus Y gametologs have diverged in function and prioritize specific gametolog pairs for future targeted experimental studies.

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Fig. 1: Overview of the study design.
Fig. 2: Gametolog gene pairs show prominent functional divergence between males and females.
Fig. 3: Within-pair functional divergence is predicted by regulatory and structural divergence between the X and Y members.
Fig. 4: Genes showing asymmetric coupling to X versus Y gametologs are numerous and enriched within specific biological pathways.
Fig. 5: Asymmetric coupling to the gametologs is related to sex differences in gene expression, co-expression and genetic contributions to ASD.

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Data availability

The data used for the analyses described in this manuscript were obtained from the GTEx Project (dbGaP accession no. phs000424/GRU).

Code availability

All code used to produce the results in this manuscript is available via GitHub at github.com/ardecasien/gametologs.

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Acknowledgements

We thank N. Snyder-Mackler for feedback on earlier versions of this manuscript and L. Lacbawan for helping us create Fig. 1. The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by National Cancer Institute (NCI), National Human Genome Research Institute (NHGRI), National Heart, Lung, and Blood Institute (NHLBI), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH) and National Institute of Neurological Disorders and Stroke (NINDS). The data used for the analyses described in this manuscript were obtained from dbGaP (accession no. phs000424/GRU). This research was supported (in part) by the Intramural Research Program of the NIMH (1ZIAMH002949-09).

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Authors and Affiliations

  1. Section on Developmental Neurogenomics, Human Genetics Branch, NIMH IRP, NIH, Bethesda, MD, USA

    Alex R. DeCasien, Kathryn Tsai, Siyuan Liu & Armin Raznahan

  2. Computational and Evolutionary Neurogenomics Unit, Laboratory of Neurogenetics, NIA IRP, NIH, Bethesda, MD, USA

    Alex R. DeCasien

  3. Data Science and Sharing Team, NIMH IRP, NIH, Bethesda, MD, USA

    Adam Thomas

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Contributions

A.R. and A.R.D. conceived and designed the study. A.R. oversaw the study. A.T. facilitated access to the data. A.R.D. and K.T. analysed the data. S.L. provided analytical support. A.R.D. and A.R. led the writing of the manuscript, and all authors provided valuable feedback and advice during its preparation.

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Correspondence to Alex R. DeCasien or Armin Raznahan.

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Extended data

Extended Data Fig. 1 Methods diagram.

a. Bottom portion of Fig. 1. b. Methods for estimating the significance of asymmetric coupling (overall and per pair) using the CLIP method. c. Method for calculating overall asymmetric coupling.

Extended Data Fig. 2 Mean adjusted expression ratios for each gametolog pair in each tissue.

Comparisons are shown between MX versus FXX (a), MXY versus FXX (b), and MX versus MY (c). Note these results are consistent with those presented by Godfrey and colleagues18.

Extended Data Fig. 3 Clustering of tissues according to functional divergence values.

Hierarchical clustering dendrograms of tissues for between-sex CFD (aCFDXXF–XYM) (a), within-pair absolute CFD (aCFDXM–YM) (b), and within-pair signed CFD (sCFDXM–YM) (c). Red values are AU (Approximately Unbiased) p-values and green values are BP (Bootstrap Probability) values (two-sided) (Methods).

Extended Data Fig. 4 Comparisons between CFD measures calculated using all genes or autosomal genes only.

a. Figure 2c using autosomal genes only. Mean (± standard error) between-sex functional divergence measures per tissue (averaged across gametolog pairs; N = 11-14 pairs, see Supplementary Table 2). Open squares indicate tissues where gametologs exhibit higher mean normalized aCFDXXF–XYM values compared to a null distribution (two-sided; padj < 0.05; Methods). Filled circles indicate tissues where normalized aCFDXXF–XYM values are significantly higher than normalized aCFDXXF–XM values (paired t-tests: padj < 0.05, Methods). Filled squares indicate tissues where gametologs exhibit higher mean normalized aCFDXXF–XM values compared to a null distribution (padj < 0.05, Methods). b-f. Top: aCFDXXF–XYM (b), sCFDXXF–XYM (c), aCFDXXF–XM (d), aCFDXM–YM (e) or sCFDXM–YM (f) per pair and tissue using autosomal genes only (y-axis) or all genes (x-axis). Bottom: histograms of the difference between aCFDXXF–XYM (b), sCFDXXF–XYM (c), aCFDXXF–XM (d), aCFDXM–YM (e) or sCFDXM–YM (f) values estimated using all genes or autosomal genes only (> 0 = higher values when using all genes).

Extended Data Fig. 5 Gametolog X-Y functional divergence predicts between-sex functional divergence.

a. Figure 2e within each tissue. Regression lines are provided for each tissue (black lines, confidence intervals are shaded) b. Between-sex signed co-expression fingerprint divergence (sCFDXXF–XYM) modeled as a function of within-pair signed co-expression fingerprint divergence in males (sCFDXM–YM). Regression lines are provided for each tissue (see legend) and across all data points (black line, confidence interval is shaded). Pearson’s correlation value and associated p-value are shown for the latter.

Extended Data Fig. 6 Regulatory and structural similarity measures.

a. Correlations across regulatory structural dissimilarity measures. Darker blue = more positive correlation; darker red = more negative correlation. b. Structural dissimilarity measures grouped by evolutionary strata (see Fig. 3b or Supplementary Table 5 for N pairs per strata). Data and colors match those in Fig. 3b. Boxplots depict medians (horizonal lines), interquartile ranges [IQRs] (boxes), 1.5*IQRs (whiskers), and outliers (points). c. Within-pair functional divergence aCFDXM–YM (across all pairs and tissues) grouped by evolutionary strata (see Fig. 3b or Supplementary Table 5 for N pairs per strata; see Supplementary Table 2 for N tissues per pair). Boxplots depict medians (horizonal lines), interquartile ranges [IQRs] (boxes), 1.5*IQRs (whiskers), and outliers (points). d. Within-pair functional divergence aCFDXM–YM (across all tissues) grouped by evolutionary strata and gametolog pair (see legend) (see Supplementary Table 2 for N tissues per pair). Boxplots depict medians (horizonal lines), interquartile ranges [IQRs] (boxes), 1.5*IQRs (whiskers), and outliers (points).

Extended Data Fig. 7 Relationships between X-Y gemetolog expression/co-expression and functional divergence.

a. X–Y co-expression values in the current study versus those estimated by Godfrey and colleagues18. We recomputed X–Y co-expression values to be comparable to our estimates of functional divergence (aCFDXXF–XYM and sCFDXXF–XYM). Differences between X–Y co-expression values across studies are the result of methodological differences, as our study: i) used a newer version of the GTEx data (v8 versus v7); ii) removed age effects when calculating adjusted expression levels (Methods); and iii) normalized co-expression values by expression level using spatial quantile normalization (Methods). Regression lines are provided for each tissue (see legend) and across all data points (black line, confidence interval is shaded). These values are highly similar (ρ = 0.617, p < 2.2e-16; linear model: slope = 0.418; p < 2.2e-16) across pair–tissue combinations. Spearman’s rank order correlation and the corresponding p-value are provided. b. aCFDXXF–XYM versus X–Y member co-expression. Regression lines are provided for each tissue (see legend) and across all data points (black line, confidence interval is shaded). Absolute within-pair divergence (aCFDXM–YM) necessarily exhibits a strong negative correlation with the level of co-expression between the X and Y members themselves (within each pair) (ρ = -0.768, p < 2.2e-16). Spearman’s rank order correlation and the corresponding p-value are provided. c. sCFDXXF–XYM versus X–Y member co-expression. Regression lines are provided for each tissue (see legend) and across all data points (black line, confidence interval is shaded). Note that relative to aCFDXXF–XYM (Extended Data Fig. 7b), this relationship is relatively muted for signed divergence (sCFDXM–YM) (ρ = -0.172, p < 0.001). Spearman’s rank order correlation and the corresponding p-value are provided. d. aCFDXM–YM versus the median Y/X expression ratio. Regression lines are provided for each tissue (see legend) and across all data points (black line, confidence interval is shaded). Spearman’s rank order correlation and the corresponding p-value are provided. e. sCFDXM–YM versus the median Y/X expression ratio. Regression lines are provided for each tissue (see legend) and across all data points (black line, confidence interval is shaded). Spearman’s rank order correlation and the corresponding p-value are provided. f. Differences in X–Y expression variance versus differences in X–Y mean expression. Regression lines are provided for each tissue (see legend) and across all data points (black line, confidence interval is shaded). Spearman’s rank order correlation and the corresponding p-value are provided. g. Extended Data Fig. 7d excluding TMSB4X/Y. Regression lines are provided for each tissue (see legend) and across all data points (black line, confidence interval is shaded). Spearman’s rank order correlation and the corresponding p-value are provided. h. Extended Data Fig. 7e excluding TMSB4X/Y. Regression lines are provided for each tissue (see legend) and across all data points (black line, confidence interval is shaded). Spearman’s rank order correlation and the corresponding p-value are provided. i. Extended Data Fig. 7f excluding TMSB4X/Y. Regression lines are provided for each tissue (see legend) and across all data points (black line, confidence interval is shaded). j. Y/X expression ratios (log2) across all pair–tissue combinations. Purple = Y > X expression. Red = X > Y expression.

Extended Data Fig. 8 Distributions of asymmetric coupling.

a. Figure 4d excluding tissue-specific genes. Color indicates direction of coupling (see Fig. 4b legend). Note that although the modal number of tissues in which genes showed significant X- or Y-biased coupling was one (Fig. 4d), the current plot suggests that this pattern is driven by genes with tissue-specific expression. b. Count of genes with significant asymmetric coupling (CLIP padj < 0.05) to a given gametolog pair in a maximum of N tissues. Color indicates direction of coupling (see Fig. 4b legend). c. Extended Data Figure 8b excluding tissue-specific genes. Color indicates direction of coupling (see Fig. 4b legend). d. Count of genes with significant asymmetric coupling (CLIP padj < 0.05) with a maximum of N pairs within a given tissue. Color indicates direction of coupling (see Fig. 4b legend). Note that, while the modal number of gametolog pairs that genes were asymmetrically coupled to (across all tissues) was eight (Fig. 4d), the modal number of pairs within a given tissue was only two (shown here). e. Number of genes with significant (CLIP padj < 0.05) asymmetric coupling for each pair–tissue using the subsamples (N = 66 males, Methods; Supplementary Tables 9,10) versus the entire sample (ρ = 0.598, p < 2.2e-16). Regression lines with confidence intervals are shown. f. Number of genes with significant (CLIP padj < 0.05) asymmetric coupling for each pair using the subsamples (N = 66 males, Methods; Supplementary Tables 9,10) versus the entire sample (ρ = 0.981, p = 1.124e-10). Regression lines with confidence intervals are shown. g. Number of genes with Methods (CLIP padj < 0.05) asymmetric coupling for each tissue using the subsamples (N = 66 males, Methods; Supplementary Tables 9,10) versus the entire sample (ρ = 0.428, p = 0.005). Regression lines with confidence intervals are shown. h. Boxplots of the proportion of pair-tissue combinations in which genes are asymmetrically coupled (CLIP padj < 0.05). ANOVA p = 1.08e-05; Tukey’s HSD padj = 5.93e-05 for X > autosomal. Boxplots depict medians (horizonal lines), interquartile ranges [IQRs] (boxes), 1.5*IQRs (whiskers), and outliers (points). i. Boxplots of asymmetric coupling values among autosomal, X chromosome, and Y chromosome genes with significant asymmetric coupling (CLIP padj < 0.05). Values are shown for each gametolog pair (see Supplementary Table 8 for N genes x tissues per pair). Colored dots on the x-axis indicate significance of comparisons (see bottom legend, Supplementary Table 11; Tukey’s HSD results are only shown for pairs in which ANOVA pad < 0.05). Boxplots depict medians (horizonal lines), interquartile ranges [IQRs] (boxes), 1.5*IQRs (whiskers), and outliers (points). j. Boxplots of asymmetric coupling values among autosomal, X chromosome, and Y chromosome genes with significant asymmetric coupling (CLIP padj < 0.05). Values are shown for each tissue (see Supplementary Table 8 for N genes x pairs per tissue). Colored dots on the x-axis indicate significance of comparisons (see bottom legend, Supplementary Table 11; Tukey’s HSD results are only shown for tissues in which ANOVA padj < 0.05). Non-gametolog Y chromosome genes show strong Y-biased coupling in the testes (for example, HSFY1/2) and stomach (for example, DAZ1/2/4). Boxplots depict medians (horizonal lines), interquartile ranges [IQRs] (boxes), 1.5*IQRs (whiskers), and outliers (points).

Extended Data Fig. 9 Delineating the polarity and biological patterning of X-Y gametolog functional divergence.

a. PCA of asymmetric coupling values across all pairs–tissues (represented by each point, see legend). b. tSNE of asymmetric coupling values across all pairs–tissues (represented by each point, see legend). c. UMAP of asymmetric coupling values across tall pairs–tissues (represented by each point, see legend). d. PCA of asymmetric coupling values across all pairs–tissues (represented by each point, see legend). Similar tissues have been collapsed (Methods). e. tSNE of asymmetric coupling values across all pairs–tissues (represented by each point, see legend). Similar tissues have been collapsed (Methods). f. UMAP of asymmetric coupling values across all pairs–tissues (represented by each point, see legend). Similar tissues have been collapsed (Methods). g. Mean asymmetric coupling values with N = 15 gametolog pairs (excluding AMELX/Y and RPS4X/Y2, which are not expressed) for genes in each cluster (averaged across tissues). N = 8 clusters were derived from N = 11,498 genes whose asymmetric coupling values were predicted by gametolog pair only (see Fig. 4g) (clusters with < 20 genes were removed). Clusters and pairs are ordered according to hierarchical clustering. Asterisks indicate padj < 0.05 (versus null, two-sided; Methods). h. Extended Data Fig. 9g, but with mean sCFDXM–YM values shown for each tissue. i. Extended Data Fig. 9g, but with pairs ranked within each cluster according to their mean sCFDXM–YM values. j. Top enriched biological processes and associated −log10(p-values) for each cluster. Top 2 categories are shown for each cluster. k. Top enriched cellular compartments and associated −log10(p-values) for each cluster. Top 2 categories are shown for each cluster. l. Similar to Extended Data Fig. 9g, but for genes whose expression is predicted by tissue only (see Supplementary Table 13, Column L). Mean asymmetric coupling values in each tissue for genes in each cluster. N = 3 clusters were derived from N = 40 genes whose asymmetric coupling values were predicted by tissue only (Fig. 4g). Clusters and pairs are ordered according to hierarchical clustering. Asterisks indicate padj < 0.05 (versus null, two-sided; Methods). m. Extended Data Fig. 9l, but with mean sCFDXM–YM values shown for each pair. n. Extended Data Fig. 9l, but with tissues ranked within each cluster according to their mean sCFDXM–YM values. o. Extended Data Fig. 9j, but for genes whose expression is predicted by tissue only (see Supplementary Table 13, Column L). Top enriched biological processes and associated −log10(p-values) for each cluster. Top 4 categories are shown for each cluster. p. Extended Data Fig. 9k, but for genes whose expression is predicted by tissue only (see Supplementary Table 13, Column L). Top enriched cellular compartments and associated −log10(p-values) for each cluster. Top 4 categories are shown for each cluster. q. Similar to Extended Data Fig. 9g, but for genes whose expression is predicted by both pair and tissue (see Supplementary Table 13, Column M). Mean asymmetric coupling values for each pair (top) or tissue (bottom) for genes in each cluster. N = 5 clusters were derived from N = 1,141 genes whose asymmetric coupling values were predicted by pair and tissue (Fig. 4g). Clusters and pairs are ordered according to hierarchical clustering. Asterisks indicate padj < 0.05 (versus null, two-sided; Methods). r. Extended Data Fig. 9q, but with mean sCFDXM–YM values shown for each tissue (top) or pair (bottom). s. Similar to Extended Data Fig. 9j, but for genes whose expression is predicted by pair and tissue (see Supplementary Table 13, Column M). Top enriched biological processes and associated −log10(p-values) for each cluster. Top 2 categories are shown for each cluster. t. Similar to Extended Data Fig. 9k, but for genes whose expression is predicted by pair and tissue (see Supplementary Table 13, Column M). Top enriched cellular compartments and associated −log10(p-values) for each cluster. Top 2 categories are shown for each cluster.

Extended Data Fig. 10 X-Y functional divergence predicts sex differences in expression and co-expression.

a. Figure 5a with tissue specific regression lines. b. Enrichment results between overall asymmetric coupling and sex-biased co-expression (Methods). OR = odds ratio. c. Mean scaled co-expression values between all pairs of X-biased genes and Y-biased genes in each tissue in males (green) versus females (yellow) (tissue-specific results in Supplementary Table 23). d. Data used for Fig. 5d. All pair-level asymmetric coupling values for N = 24 ASD risk genes with significant overall asymmetric coupling (CLIP padj<0.05) in BA24 are shown (see right column for direction of overall asymmetric coupling; ASD risk genes are separated by functional category). Only significant pair-level values (CLIP padj<0.05) are included in Fig. 5d, and in this figure they are outlined in black.

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DeCasien, A.R., Tsai, K., Liu, S. et al. Evolutionary divergence between homologous X–Y chromosome genes shapes sex-biased biology. Nat Ecol Evol 9, 448–463 (2025). https://doi.org/10.1038/s41559-024-02627-x

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