Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery

Scott EM
Halees A
Itan Y
Spencer EG
He Y
Azab MA
Gabriel SB
Belkadi A
Boisson B
Abel L
Clark AG; Greater Middle East Variome Consortium
Alkuraya FS
Casanova JL
Gleeson JG
Rahim SA
Abdel-Hadi S
Abdel-Salam G
Abdel-Salam E
Abdou M
Abhytankar A
Adimi P
Ahmad J
Akcakus M
Aksu G
Hajjar SA
Juamaah SA
Muhsen SA
Sannaa NA
Tameni SA
Al-Aama J
Al-Allawi N
Al-Baradie R
Al-Gazali L
Al-Hashem A
Al-Herz W
Al-Jeaid D
Al-Tawari A
Alangari A
Alcais A
S AlFawaz T
Alsum Z
Ammar-Khodja A
Amouian S
Arikan C
Aryani O
Celik FC
Cipe FE
Clark G
Cobat A
Comu S
Condie A
Condino-Neto A
Desai M
Dobyns W
Dogu F
Domaia M
Dorum M
Egritas O
Azbaoui SE
Baghdadi JE
Ruby ME
El-Harouni A
Fenerci E
Gelik U
Koul R
Mahlaoui N
Mekki N
Patiroglu T
Koc ZP
Pellier I
Picard C
Puel A
Raas-Rothschild A
Rajab A
Raoult D
Reisli I
Rezaei N
Sabri A
Saleem L
AlSediq NS
Shakankiry H
Shang L
Shehata N
Shkalim V
Softah A
Sogaty S
Sonmez-Aunaci F
Sztriha L
Taibi-Berrah L
Vogt G
Walsh C
Zaki M
Zhang SY

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia, has resulted in an elevated burden of recessive disease. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variationdue to classically theorized 'genetic purging'. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics.


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