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 and track disease inheritance patterns. 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 identifying a source for each IBD segment and assembling IBD segments placed within each ancestral individual. 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 12 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 224 ancestral individuals per chromosome. For these ancestral individuals, on average we reconstruct 79% of their haplotypes. We also identify a region on chromosome 16 that is difficult to reconstruct—we find that this region harbors a short Amish-specific copy number variation and the gene HYDIN. 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.

Fully exploiting SNP arrays: a systematic review on the tools to extract underlying genomic structure

“…Software devoted to the analysis of population structure and ancestry was not only used to infer population patterns [ 40 , 160–163 ] but also to support studies of diseases and traits in which population admixture and ancestry play determinant roles [ 164–173 ]. The same could be observed for IBD detection, with some articles centered on population structure [ 55 , 174–176 ] and others on practical applications [ 177 , 178 ]. In ancestry studies, more than one algorithm was usually applied, and we did not observe a clear trend towards any of the tools, as almost all of them had been referenced during the analyzed period.…”

Long Runs of Homozygosity Are Correlated with Marriage Preferences across Global Population Samples

“…First, we carried out simulations to investigate the effect of degree (proportion of cousin unions) and duration (number of generations) of consanguinity on the distribution of ROH. We used cousin-sim (Finke et al 2021) to generate pedigrees, each of which was initialized with 1,000 unrelated founders and 1,000 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 (NIPS and ICF 2019).…”

Reconstructing parent genomes using siblings and other relatives

“…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.…”