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

Abstract

Deleterious variants in DNA damage repair (DDR) system can cause genome instability and increase cancer risk. In this study, we analyzed the deleterious variants in DDR system in 16 ethnic human populations. From the genetic variants in 169 DDR genes involved in nine DDR pathways collected from 158,612 individuals of different ethnic background, we identified 1,781 deleterious variants in 81 DDR genes in eight DDR pathways (https://genemutation.fhs.um.edu.mo/dbddr-global/). Our analysis showed although the quantity of deleterious variants was loaded at a similar level, the landscape of the variants differed substantially among different populations that two-third of the variants were present in single ethnic populations, and the rest was mostly shared between the populations with closer geographic and genetic relationship. The highly ethnic-specific DDR deleterious variation suggests its potential relationship with different disease susceptibility in ethnic human populations.

Figure 1.. Frequency of deleterious variant distribution in DNA damage repair (DDR) genes.

It shows the distribution frequency of the deleterious variants in 81 DDR genes in the 159,612 individuals included in the study. The dots in DDR pathways show the gene(s) in DDR pathways affected by the variants. Pink dot refers to the high frequent variant-affected top 10 DDR genes of BRCA2, ATM, BRCA1, FANCA, RAD50, PALB2, MSH6, BRIP1, CHEK2, and PMS2 and their corresponding pathways. BAR chart shows the distribution of minor allele frequency (%) for the 1,781 deleterious variants. HR, homologous recombination; FA, fanconi anemia; NER, nucleotide excision repair; MMR, mismatch repair; BER, base excison repair; NHEJ, non-homologous end joining; DNA rep, DNA replication; DNA response, DNA damage response.

Figure 2.. DNA damage repair deleterious variants distributed in human populations.

(A) Ethnic specificity of DNA damage repair deleterious variants. It shows that 1,195 of the 1,781 variants were present in single populations, and the rest were shared mostly between two populations. (B) DDR variants sharing between non-Africa and African populations. (C) BRCA1/2 variant deleterious variants sharing between different populations. (D) MMR variants sharing between different populations. The different sharing rates between BRCA and MMR variants showed the more variable BRCA deleterious variants than MMR deleterious variants. DV, deleterious variants.