Challenges of accurately estimating sex-biased admixture from X chromosomal and autosomal ancestry proportions

Abstract

Sex-biased admixture can be inferred from ancestry-specific proportions of X chromosome and autosomes. In a paper published in the American Journal of Human Genetics, Micheletti et al.¹ used this approach to quantify male and female contributions following the transatlantic slave trade. Using a large dataset from 23andMe, they concluded that African and European contributions to gene pools in the Americas were much more sex biased than previously thought. We show that the reported extreme sex-specific contributions can be attributed to unassigned genetic ancestry as well as the limitations of simple models of sex-biased admixture. Unassigned ancestry proportions in the study by Micheletti et al. ranged from ∼1% to 21%, depending on the type of chromosome and geographic region. A sensitivity analysis illustrates how this unassigned ancestry can create false patterns of sex bias and that mathematical models are highly sensitive to slight sampling errors when inferring mean ancestry proportions, making confidence intervals necessary. Thus, unassigned ancestry and the sensitivity of the models effectively prohibit the interpretation of estimated sex biases for many geographic regions in Micheletti et al. Furthermore, Micheletti et al. assumed models of a single admixture event. Using simulations, we find that violations of demographic assumptions, such as subsequent gene flow and/or sex-specific assortative mating, may have confounded the analyses of Micheletti et al., but unassigned ancestry was likely the more important confounding factor. Our findings underscore the importance of using complete ancestry information, sufficiently large sample sizes, and appropriate models when inferring sex-biased patterns of demography. This Matters Arising paper is in response to Micheletti et al.,¹ published in American Journal of Human Genetics. See also the response by Micheletti et al.,² published in this issue.

Keywords: Americas; admixture; genetic ancestry; mathematical models; population genetics; sex bias; slave trade.

Figure 1

A wide range of sex ratios is plausible in geographic regions with substantial amounts of unassigned ancestry Missing ancestry in the study by Micheletti et al. for the Latin Caribbean, central South America, northern South America, and Central America was distributed in 1% increments such that ancestry proportions add up to 100%. Corresponding sex ratios were then computed using the equilibrium model (Equation 1). Ancestry proportions that led to model failure were discarded. The boxes represent the inter-quartile range, with the median sex ratio indicated by the line spanning the box. The whiskers represent the range between the 2.5^th and 97.5^th percentile. Note that the x axis is logarithmic to show the full range of possible sex ratios but that s^f/s^m < 0.1 and s^f/s^m > 10 are improbable. The clustering of the sex ratios is due to increments of 0.01 that were used for distributing unassigned ancestry. Black triangles correspond to sex ratios estimated from mean ancestry proportions reported by Micheletti et al. (Table 1). If no black triangle is shown, model failure was observed.

Figure 2

Estimates of sex-biased admixture from X chromosomes and autosomes are highly sensitive to small differences in ancestry proportions s^f/s^m refers to the ratio of female to male contributions, X chromosomal ancestry proportions are represented by H^X, and autosomal ancestry proportions are represented by H^A. (A) Presuming an autosomal ancestry of 0.123 (i.e., the autosomal African ancestry proportion in central South America reported by Micheletti et al.¹), X chromosomal ancestry proportions must be in the interval [0.082, 0.164] under a demographic model of a single admixture event. X chromosome-related ancestries outside of this range cause negative sex ratios (i.e., model failure). The black triangle indicates the sex ratio inferred based on the ancestry proportions reported by Micheletti et al. for African ancestry in central South America (Table 1). (B) Exploration of parameter space for different combinations of autosomal and X chromosomal ancestry proportions. Scenarios that yield female-biased sex ratios (s^f/s^m > 1) are colored green, male-biased sex ratios (0 < s^f/s^m < 1) are colored blue, and model failures (s^f/s^m < 0) are colored gray. Black triangles indicate ancestry proportions reported by Micheletti et al. (Table 1). Most cases of model failure are observed when inferred ancestry proportions are small (black triangles in gray area). No triangle is shown when either the X chromosomal or autosomal ancestry proportion was below 0.05.

Figure 3

Large sample sizes are required to confidently estimate the extent of sex-biased admixture using X chromosomal and autosomal ancestry proportions Admixture in the Americas was simulated as three-way combinations of source population 1 (S₁; blue), source population 2 (S₂; orange), and source population 3 (S₃; green) with female-biased contributions from S₁ and S₃ (i.e., 2 and 1.25 females to 1 male, respectively) and male-biased contributions from S₃ (i.e., two males to one female). The simulated admixture proportions were 1/6, 1/3, and 1/2 for S₁, S₂, and S₃, respectively. The crosses indicate the simulated sex ratio (s^f/s^m), filled circles indicate mean estimates, and error bars represent 95% confidence intervals.