The impact of the Turkish (TK) population variome on the genomic architecture of rare disease traits

Abstract

We investigated the influences of admixture and consanguinity on the genetic architecture of disease by generating a database of variants derived from exome sequencing (ES) of 853 unrelated Turkish (TK) individuals with different disease phenotypes. We observed that TK genomes are more similar to Europeans with 69.3% of the unique variants (N = 356,613) not present in the Greater Middle Eastern variome.We found higher inbreeding coefficient values in the TK cohort correlating with a larger median span of long-sized (>1.606 Mb) runs of homozygosity (ROH). We show that long-sized ROHs arose from recently configured haplotypes and are enriched for rare homozygous deleterious variants. Such haplotypes, and the combinatorial effect of their embedded ultra-rare variants, provide the most explanatory molecular diagnoses for the TK individuals' observed disease traits. Such haplotype evolution results in homozygosity of disease associated haplotypes due to identity-by-descent in a family or extended clan.Genomics hypothesis (Lupski et al., 2011), the notion that novel rare variant alleles arising within a patient, or the recent past generations of a family or more extended clan, significantly contribute to disease in populations. These data underscore the value of studying alternative population substructures that present with high levels of both admixture and consanguinity to elucidate the molecular mechanisms and genetic and genomic architecture underlying disease in populations. Results The Turkish (TK) variomeAfter removing related individuals from the Baylor Hopkins Center for Mendelian Genomics (BHCMG) database, exomes from 4,933 unrelated individuals remained for further analyses. From this data set, we used principal component analysis (PCA) to investigate the population structure between our TK and non-TK cohorts in comparison to the African, Asian, and European population samples from the 1000 Genomes Project. The first main principal component axis (PC1) separated the African samples from the Asian, the European populations and the TK and non-TK cohorts of the BHCMG samples ( Figure 1A). The second main principal component axis (PC2) further separated the Asian samples from the European and the TK and non-TK groups of the BHCMG cohort. These studies showed that the TK genomes were distinct from the African and Asian populations, and more similar to the variomes of European samples compared to the non-TK samples that spread out across different populations ( Figure 1A and Supplementary Figure 1).

Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits

“…It is expected that all patients with biallelic disease variants fall into three categories (1) HMZ: those affected with homozygous small variants possibly from a close-or distant-consanguineous relationship, (2) SNV+SNV: those affected with compound heterozygous small variants, and (3) NAHR+SNV: those affected with a large deletion in trans with a small variant. We anticipate that category #1-HMZ accounts for a substantial proportion, demonstrating the well-established robustness of autozygosity mapping as a method for allelic and new recessive gene discovery (as populational rare alleles can be escalated to much higher clan allele frequency) (Coban-Akdemir et al 2020). In outbred pedigrees and populations corresponding to categories #2-SNV+SNV and #3-NAHR+SNV, our modeling from the NIRD hypothesis is that #3-NAHR+SNV should account for a higher fraction.…”

“…We anticipate that category #1 accounts for a substantial proportion, demonstrating the robustness of the autozygosity mapping method in new recessive gene discovery (as populational rare alleles can be escalated to much higher clan allele frequency). 5 In outbred populations corresponding to categories #2 and #3, the working hypothesis is that #3 should account for a much higher fraction. Otherwise, the opposing trend may suggest that our current disease gene/allele discovery efforts are not exploiting the large deletion allele to the fullest extent that a ‘human haploid genetics’ approach might allow.…”

“…4 ; 5 Thus, the probability of ascertaining patients with the recessive disorder increases exponentially, even when all existing alleles are ultra-rare in sampling the general population. 6…”

“…In this circumstance, the allele pool shrinks to the Clan of the patient's extended family, which dramatically escalates the effective disease-allele frequency (Gonzaga-Jauregui et al 2020;Alkuraya 2021). Thus, the probability of ascertaining patients with the recessive trait disorder increases exponentially, even when all existing alleles are ultra-rare in sampling the general population (Coban-Akdemir et al 2020).…”

“…In this circumstance, the allele pool shrinks to the Clan of the patient's extended family, which dramatically escalates the effective disease-allele frequency compared to the baseline allele frequency in the general population (Gonzaga-Jauregui et al 2020;Alkuraya 2021). Thus, the probability of ascertaining patients with a recessive trait disorder increases exponentially, because the sampling of the second allele occurs within the Clan rather than the general population (Coban-Akdemir et al 2020). Similarly, focusing on a specific geographic or ethnic population is another effective strategy, often attributed to available founder mutation alleles in the population studied (Gonzaga-Jauregui et al 2020); the Puerto Rican founder allele, and specifically the COL27A1 founder in a geographic isolation bottleneck and Steel syndrome on the island of Puerto Rico, was informative.…”