Crossover interference and sex-specific genetic maps shape identical by descent sharing in close relatives

Abstract

Simulations of close relatives and identical by descent (IBD) segments are common in genetic studies, yet most past efforts have utilized sex averaged genetic maps and ignored crossover interference, thus omitting features known to affect the breakpoints of IBD segments. We developed Ped-sim, a method for simulating relatives that can utilize either sex-specific or sex averaged genetic maps and also either a model of crossover interference or the traditional Poisson model for inter-crossover distances. To characterize the impact of previously ignored mechanisms, we simulated data for all four combinations of these factors. We found that modeling crossover interference decreases the standard deviation of the IBD proportion by 10.4% on average in full siblings through second cousins. By contrast, sex-specific maps increase this standard deviation by 4.2% on average, and also impact the number of segments relatives share. Most notably, using sex-specific maps, the number of segments half-siblings share is bimodal; and when combined with interference modeling, the probability that sixth cousins have non-zero IBD ranges from 9.0 to 13.1%, depending on the sexes of the individuals through which they are related. We present new analytical results for the distributions of IBD segments under these models and show they match results from simulations. Finally, we compared IBD sharing rates between simulated and real relatives and find that the combination of sex-specific maps and interference modeling most accurately captures IBD rates in real data. Ped-sim is open source and available from https://github.com/williamslab/ped-sim. Short title: Crossover interference and sex-specific maps shape IBD distributionsSimulations are ubiquitous throughout statistical genetics in order to generate data with known properties, enabling tests of inference methods and analyses of real world processes in settings where experimental data are challenging to collect. Simulating genetic data for relatives in a pedigree requires the synthesis of chromosomes parents transmit to their children. These chromosomes form as a mosaic of a given parent's two chromosomes, with the location of switches between the two parental chromosomes known as crossovers. Detailed information about crossover generation based on real data from humans now exists, including the fact that men and women have overall different rates (women produce ∼1.6 times more crossovers) and that real crossovers are subject to interference-whereby crossovers are further apart from one another than expected under a model that selects their locations randomly. Our new method, Ped-sim, can simulate pedigree data using these less commonly modeled crossover features, and we used it to evaluate the importance of sex-specific rates and interference in real data. These comparisons show that both factors shape the amount of DNA two relatives share identically, and that their inclusion in models of crossover better fit data from real relatives.

Recombination and selection against introgressed DNA

“…Veller et al (2019) demonstrated that interference among crossovers-by spreading them out more evenly along chromosomes-increases the amount of genetic shuffling that they cause (increasingr and analogs). This provides an intuitive explanation of the result of Caballero et al (2019).…”

“…Both factors decrease the total amount of genetic shuffling ). This explains the observation of Caballero et al (2019) that relatives who are related predominantly via males have a higher variance of genetic relatedness than relatives related predominantly via females.…”

“…Crossover interference. It has recently been shown, by computer simulation of various forms of crossover patterning along chromosomes, that crossover interference tends to decrease the variance of genetic relatedness between relatives (Caballero et al 2019). Veller et al (2019) demonstrated that interference among crossovers-by spreading them out more evenly along chromosomes-increases the amount of genetic shuffling that they cause (increasingr and analogs).…”

“…This formulation allows effects on the variance of genetic relatedness to be reinterpreted-often more intuitively-in terms of effects on aggregate genetic shuffling. For example, it has recently been shown that crossover interference decreases the variance of genetic relatedness (Caballero et al 2019). This can be explained by the intuitive fact that crossover interference, by spreading crossovers out evenly along chromosomes, increases the amount of genetic shuffling that they cause (Gorlov and Gorlova 2001;Veller et al 2019).…”

Distinguishing pedigree relationships using multi-way identical by descent sharing and sex-specific genetic maps

“…In general, the female map has a greater genetic length (1.6× on the autosomes) than the male map, but the male map is locally longer near the telomeres 18 . The autosomal length difference between the maps affects the number of crossovers-and thus the number of IBD segments-transmitted through male or female meioses 24 . Accordingly, the distributions of IBD segment numbers differ meaningfully between paternal and maternal HS and GP relatives ( Figure S2), to the extent that limited classification is in principle possible using segment number alone.…”