Human BRCA pathogenic variants were originated during recent human history

Abstract

BRCA1 and BRCA2 (BRCA) play essential roles in maintaining genome stability. BRCA germline pathogenic variants increase cancer risk. However, the evolutionary origin of human BRCA pathogenic variants remains largely elusive. We tested the 2,972 human BRCA1 and 3,652 human BRCA2 pathogenic variants from ClinVar database in 100 vertebrates across eight clades, but failed to find evidence to show cross-species evolution conservation as the origin; we searched the variants in 2,792 ancient human genome data, and identified 28 BRCA1 and 22 BRCA2 pathogenic variants in 44 cases dated from 45,000 to 300 yr ago; we analyzed the haplotype-dated human BRCA pathogenic founder variants, and observed that they were mostly arisen within the past 3,000 yr; we traced ethnic distribution of human BRCA pathogenic variants, and found that the majority were present in single or a few ethnic populations. Based on the data, we propose that human BRCA pathogenic variants were highly likely arisen in recent human history after the latest out-of-Africa migration, and the expansion of modern human population could largely increase the variation spectrum.

Distinct landscapes of deleterious variants in DNA damage repair system in ethnic human populations

“…This is evidenced by the fact that nearly all currently known BRCA founder mutations determined by haplotyping were young, for example, BRCA1 c.3228_3229del in Italian was arisen 3,225 yr ago (Laitman et al, 2013); of the three BRCA founder mutations in Ashkenazi Jewish population, BRCA1 185delAG(c.68_69del) was arose 1,500-750 yr ago (Hamel et al, 2011), BRCA1 5382insC(c.5266dup) 1,800 yr ago (Neuhausen et al, 1998), and BRCA2 6174delT(c.5946del) 580 yr ago (Zeegers et al, 2004); BRCA2 c.9118-2A>G, a founder mutation in Icelander population, was arisen only 220-144 yr ago (Altmann & Gennery, 2016). Our recent study also revealed that human BRCA deleterious variants mostly arose after migration out-of-Africa and great expansion of modern human population (Li et al, 2022). This may also be related with differences of evolution selection on different DDR genes.…”

“…Two third of DDR deleterious variants were present only in single ethnic populations. It suggests that DDR deleterious variants could be most likely arisen in recent history (Keinan & Clark, 2012;Fu et al, 2013;Li et al, 2022). This is evidenced by the fact that nearly all currently known BRCA founder mutations determined by haplotyping were young, for example, BRCA1 c.3228_3229del in Italian was arisen 3,225 yr ago (Laitman et al, 2013); of the three BRCA founder mutations in Ashkenazi Jewish population, BRCA1 185delAG(c.68_69del) was arose 1,500-750 yr ago (Hamel et al, 2011), BRCA1 5382insC(c.5266dup) 1,800 yr ago (Neuhausen et al, 1998), and BRCA2 6174delT(c.5946del) 580 yr ago (Zeegers et al, 2004); BRCA2 c.9118-2A>G, a founder mutation in Icelander population, was arisen only 220-144 yr ago (Altmann & Gennery, 2016).…”

Integration of deep learning with Ramachandran plot molecular dynamics simulation for genetic variant classification

“…However, they are not be suitable to classify the missense variants in BRCA1 and BRCA2 , as the pathogenic variants in BRCA1 and BRCA2 were mostly originated in recent human history rather than evolution conservation from other species. 52 On the contrary, DL-RP-MDS uses protein structure as the reference to identify abnormalities caused by missense variants by following the thermodynamics changes to differentiate benign and deleterious variants. Furthermore, DL-RP-MDS can tolerate the altered residues and allocate deleterious probability with high BA values.…”

Evolutionary Origin of MUTYH Germline Pathogenic Variations in Modern Humans

“…The process followed the detailed procedures described in our previous publication [ 13 ]. Briefly, the reference sequences used in annotating human MUTYH variants were: hg38 NC_000001.11 for the genomic position, NM_012222 for cDNA and NP_036354 for protein.…”