De novo mutation in ancestral generations evolves haplotypes contributing to disease

Coban Akdemir, Z.; Song, X.; Pehlivan, D.; Karaca, E.; Bayram, Y.; Gambin, T. L.; Jhangiani, S.; muzny, d. m.; Lewis, R.; Baylor Hopkins Center for Mendelian Genomics,; Liu, P.; Boerwinkle, E.; Hamosh, A.; Gibbs, R. A.; Sutton, R.; Sobreira, N.; Carvalho, C. M. B.; Posey, J.; Shaw, C. A.; Valle, D.; Lupski, J. R.

doi:10.1101/2020.04.27.064824

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bioRxiv · 10.1101/2020.04.27.064824

De novo mutation in ancestral generations evolves haplotypes contributing to disease

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Abstract

PurposeThe variome of the Turkish (TK) population, a population with a considerable history of admixture and consanguinity, has not been deeply investigated deeply for its potential impact on the genomic architecture of disease traits. MethodsWe generated and analyzed a database of variants derived from exome sequencing (ES) data of 773 TK unrelated, clinically affected individuals with various suspected Mendelian disease traits, and 643 unaffected relatives. ResultsUsing uniform manifold approximation and projection (UMAP), we showed that the TK genomes are more similar to those of Europeans and consist of two main subpopulations: clusters 1 and 2 (N=235 and 1,181) that differ in admixture proportion and variome (https://turkishvariomedb.shinyapps.io/tvdb/). Furthermore, the higher inbreeding coefficient (F) values observed in the TK affected compared to unaffected individuals correlated with a larger median span of long-sized (>2.64 Mb) runs of homozygosity (ROH) regions (p-value=2.09e-18). We show that long-sized ROHs are more likely to be formed on recently configured haplotypes enriched for rare homozygous deleterious variants in the TK-affected compared to TK-unaffected individuals (p-value= 3.35e-11). Analysis of genotype-phenotype correlations reveals that genes with rare homozygous deleterious variants in long-sized ROHs provide the most comprehensive set of molecular diagnoses for the observed disease traits with a systematic quantitative analysis of HPO (Human Phenotype Ontology) terms. ConclusionOur findings support the notion that novel rare variants on newly configured haplotypes arising within the recent past generations of a family or clan contribute significantly to recessive disease traits in the TK population.

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Coban Akdemir, Z., Song, X., Pehlivan, D., Karaca, E., Bayram, Y., Gambin, T. L., Jhangiani, S., muzny, d. m., Lewis, R., Baylor Hopkins Center for Mendelian Genomics,, Liu, P., Boerwinkle, E., Hamosh, A., Gibbs, R. A., Sutton, R., Sobreira, N., Carvalho, C. M. B., Posey, J., Shaw, C. A., Valle, D., Lupski, J. R.. 2020-04-28. De novo mutation in ancestral generations evolves haplotypes contributing to disease. https://doi.org/10.1101/2020.04.27.064824

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