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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. ### Competing Interest Statement J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals and Novartis, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. C.A.S and P.L. are employees of Baylor College of Medicine and derive support through a professional services agreement with the Baylor Genetics (BG). The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular genetic testing offered at BG (http://www.bcm.edu/geneticlabs/). JRL serves on the SAB of BG. The other authors declare no competing financial interests.

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