Ancestral Haplotype Reconstruction in Endogamous Populations using Identity-By-Descent

Abstract

In this work we develop a novel algorithm for reconstructing the genomes of ancestral individuals, given genotype or sequence data from contemporary individuals and an extended pedigree of family relationships. A pedigree with complete genomes for every individual enables the study of allele frequency dynamics and haplotype diversity across generations, including deviations from neutrality such as transmission distortion. When studying heritable diseases, ancestral haplotypes can be used to augment genome-wide association studies or compute polygenic risk scores for the reconstructed individuals.The building blocks of our reconstruction algorithm are segments of Identity-By-Descent (IBD) shared between two or more genotyped individuals. The method alternates between finding a source for each IBD segment and assembling IBD segments placed within each ancestral individual. After each iteration we perform conflict resolution to remove IBD segments that do not align with wellreconstructed haplotypes and upweight the probability that these segments should be placed in other individuals. We repeat this process until we are no longer successfully reconstructing additional ancestral haplotypes. Unlike previous approaches, our method is able to accommodate complex pedigree structures with hundreds of individuals genotyped at millions of SNPs.We apply our method to an Old Order Amish pedigree from Lancaster, Pennsylvania, whose founders came to the United States from Europe during the early 18th century. The pedigree includes 1338 individuals from the past 10 generations, 394 with genotype data. The motivation for reconstruction is to understand the genetic basis of diseases segregating in the family through tracking haplotype transmission over time. Using our algorithm thread, we are able to reconstruct an average of 230 ancestral individuals per autosome. thread was developed for endogamous populations, but can be applied to any extensive pedigree with the recent generations genotyped. We anticipate that this type of practical ancestral reconstruction will become more common and necessary to understand rare and complex heritable diseases in extended families.

Reconstructing parent genomes using siblings and other relatives

“…Its use of family-based phasing, IBD segments, and sex-specific genetic maps combine to enable precise inference of the DNA carried by the mother and father of a set of siblings. This and other related papers 1,6,7,13 demonstrate the potential for ancestor DNA reconstruction, a problem whose applications are vast. Moreover, the full promise of parent and general ancestor DNA reconstruction remains to be delivered: the completeness and accuracy of these reconstructions will continue increase as the sizes of both commercial and non-commercial genetic datasets continue to grow.…”

“…This type of reconstruction becomes more complex in small or endogamous populations and in inbred pedigrees. In these cases, the ancestor that transmitted the IBD segment may be difficult to decipher, but recent work has made progress in these settings 13 . Even when analyzing individuals from large, outbred populations, placing IBD segments on an ancestral couple using their descendants' DNA-e.g., the grandparents of two first cousins-requires IBD sharing to other relatives.…”

Long runs of homozygosity are correlated with marriage preferences across global population samples

“…We also used these simulations to calibrate the difference in consanguinity between populations that we classified as prohibiting and preferring cousin unions (see below). We used cousin-sim [14] to generate pedigrees, each of which was initialized with 500 unrelated founders and 500 individuals in subsequent generations for either 10 or 50 generations. In each generation, (c ∈ {0, 0.25, 0.5, 0.75}) of all unions were between cousins, of which 62% were first-, 23% were second-, and 15% were third-degree cousins [15].…”

Fast and Robust Identity-by-Descent Inference with the Templated Positional Burrows–Wheeler Transform

“…2019 ; Yang et al. 2019 ; Finke et al. 2020 ), and increase the accuracy of many other inferences regarding demographic history and genetic ancestry ( Palamara et al.…”