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

Zixin Qin; Teng Huang; Maoni Guo; San Ming Wang

doi:10.26508/lsa.202101319

Research Article

Published 20 May 2022. DOI: 10.26508/lsa.202101319

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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.
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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.

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Table 1.

Summary of DNA damage repair (DDR) deleterious variants in DDR pathways

DDR pathways	Number of genes	Gene with variants (%)	#Variants	Variants/gene	Benjamini–Hochberg^b
Homologous Recombination	37	21 (57)	916	44	0.433
Fanconi anemia pathway	49	30 (61)	926	31	0.103
Mismatch Repair	20	8 (36)	188	24	0.672
Nonhomologous end joining	13	7 (54)	129	18	0.876
DNA damage response	15	5 (33)	86	17	0.450
Nucleotide excision repair	41	13 (32)	163	13	0.090
Base excision repair	32	7 (22)	72	10	0.020
DNA replication	34	11 (32)	36	3	0.130
Direct reversal	3	0 (0)	0	0	0.433
Total^a	169	81 (48)	1,781	17	0.020

↵a Distinct numbers.
↵b Bold: Statistic significant between pathways.

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Table 2.

Molecular consequences of DNA damage repair deleterious variants

Molecular consequences	No.	%
Frameshift variant	711	39.9
Stop gained	527	29.6
Missense variant	200	11.2
Splice donor variant	139	7.8
Splice acceptor variant	128	7.2
Splice region variant	96	5.4
Intron variant	43	2.4
Inframe deletion	18	1.0
Start lost	17	1.0
Synonymous variant	14	0.8
Coding sequence variant	7	0.4
3 prime UTR variant	4	0.2
Inframe insertion	1	0.1
Total^a	1,781	100

↵a Distinct numbers.

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Table 3.

Number of DNA damage repair deleterious variants identified in different ethnic populations

Ethnic population	Abbreviation		#Variants	Load (P = 0.001)^a
Bulgarian	NFE-BGR	1,335	64	48
Southern European	NFE-SEU	5,805	198	34
Other non-Finnish European	NFE-ONF	16,568	420	25
Japanese	JPN	3,552	79	22
North-Western European	NFE-NWE	25,410	544	21
Chinese	CHN	10,588	216	20
South Asian	SAS	15,263	305	20
Korean	KOR	2,964	57	19
Swedish	NFE-SWE	13,067	244	19
Latino/Admixed American	AMR	17,554	312	18
African/African American	AFR	11,810	202	17
Other East Asian	EAS-OEA	7,992	133	17
Ashkenazi Jewish	ASJ	4,931	56	11
Finnish	FIN	12,554	93	7
Estonian	NFE-EST	2,418	6	2
Icelander	ICE	12,584	27	2
Total^b		158,612	1,781	11

↵a Load = variants/individuals*1,000 (P.value between group 34-17 and group 11-2).
↵b Distinct number.

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Table 4.

Comparison of DNA damage repair deleterious variants among 16 ethnic populations

Ethnicity	Total	Unshared (%)	Shared (%)^a																		Benjamini–Hochberg
Ethnicity	Total	Unshared (%)	Total	CHN	JPN	KOR	EAS-OEA	SAS	ICE	AFR	AMR	ASJ	FIN	NFE-BGR	NFE-EST	NFE-SEU	NFE-SWE	NFE-NWE	NFE-ONF	Ave.	Benjamini–Hochberg
CHN	216	94 (44)	122	-	12.3	9.0	31.1	36.9	1.6	25.4	29.5	6.6	12.3	5.7	0.8	25.4	20.5	36.1	29.5	17.7	2.74E-03
JPN	79	34 (43)	45	33.3	—	37.8	13.3	31.1	2.2	15.6	17.8	2.2	0.0	2.2	0.0	8.9	17.8	22.2	15.6	13.8	7.52E-04
KOR	57	22 (39)	35	31.4	48.6	—	14.3	14.3	2.9	20.0	20.0	2.9	5.7	5.7	0.0	14.3	11.4	11.4	17.1	13.8	7.52E-04
EAS-OEA	133	56 (42)	77	49.4	7.8	6.5	—	26.0	1.3	19.5	16.9	5.2	9.1	6.5	1.3	18.2	16.9	42.9	36.4	16.5	7.52E-04
SAS	305	148 (49)	157	28.7	8.9	3.2	12.7	—	3.2	28	36.3	6.4	11.5	9.6	0.0	25.5	25.5	47.1	35.0	17.6	2.13E-03
ICE	27	9 (33)	18	11.1	5.6	5.6	5.6	27.8	—	33.3	50	5.6	22.2	16.7	5.6	38.9	38.9	55.6	55.6	23.6	7.31E-04
AFR	202	90 (45)	112	27.7	6.2	6.2	13.4	39.3	5.4	—	33.9	5.4	13.4	12.5	0.0	24.1	27.7	50.0	43.8	19.3	8.69E-04
AMR	312	155 (50)	157	22.9	5.1	4.5	8.3	36.3	5.7	24.2	—	8.9	15.3	12.7	0.6	35.7	24.2	53.5	45.2	18.9	1.63E-03
ASJ	56	16 (29)	40	20.0	2.5	2.5	10.0	25.0	2.5	15.0	35.0	—	10.0	27.5	0.0	42.5	22.5	62.5	62.5	21.2	7.31E-04
FIN	93	19 (20)	74	20.3	0.0	2.7	9.5	24.3	5.4	20.3	32.4	5.4	—	21.6	1.4	33.8	52.7	52.7	52.7	20.9	7.52E-04
NFE-BGR	64	12 (19)	52	13.5	1.9	3.8	9.6	28.8	5.8	26.9	38.5	21.2	30.8	—	0.0	53.8	48.1	59.6	67.3	25.6	7.52E-04
NFE-EST	6	2 (33)	4	25.0	0.0	0.0	25.0	0.0	25.0	0.0	25.0	0.0	25.0	0.0	—	50.0	25.0	50.0	50.0	18.8	7.31E-04
NFE-SEU	198	63 (32)	135	23.0	3.0	3.7	10.4	29.6	5.2	20	41.5	12.6	18.5	20.7	1.5	—	33.3	59.3	54.8	21.1	1.10E-03
NFE-SWE	244	83 (34)	161	15.5	5.0	2.5	8.1	24.8	4.3	19.3	23.6	5.6	24.2	15.5	0.6	28.0	—	54.0	54.7	17.9	8.69E-04
NFE-NWE	544	238 (44)	306	14.4	3.3	1.3	10.8	24.2	3.3	18.3	27.5	8.2	12.7	10.1	0.7	26.1	28.4	—	57.8	15.4	6.14E-01
NFE-ONF	420	154 (37)	266	13.5	2.6	2.3	10.5	20.7	3.8	18.4	26.7	9.4	14.7	13.2	0.8	27.8	33.1	66.5	—	16.5	4.12E-01
Total^b	1,781	1,195 (67)	583 (33)																	18.7

↵a % = shared variants/total shared variants × 100; the rate in bold refers to the highest sharing rate among populations.
↵b Distinct number.

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Table 5.

Top 10 highly shared DNA damage repair deleterious variants in human populations

Gene	HGVSc	HGVSp	Frequency	Disease	Population shared	Number
LIG4	c.1271_1275del	p.Lys424ArgfsTer20	0.0002	LIG4-Related disorders	CHN, JPN, ICE, KOR, AFR, AMR, EAS_OEA, NFE_BGR, NFE_NWE, NFE_SEU, NFE_SWE, NFE_ONF, SAS	13
MUTYH	c.1103G>A	p.Gly368Asp	0.0030	MYH-associated_polyposis	CHN, AFR, AMR, ASJ, EAS_OEA, FIN, NFE_BGR, NFE_NWE, NFE_SEU, NFE_SWE, NFE_ONF, SAS	12
RAD50	c.2165dup	p.Glu723GlyfsTer5	0.0003	Hereditary cancer	CHN, AFR, AMR, ASJ, EAS_OEA, FIN, NFE_BGR, NFE_NWE, NFE_SEU, NFE_SWE, NFE_ONF, SAS	12
MSH6	c.3226C>T	p.Arg1076Cys	0.0001	Lynch syndrome	CHN, AFR, AMR, ASJ, EAS_OEA, NFE_BGR, NFE_NWE, NFE_SEU, NFE_SWE, NFE_ONF, SAS	11
MUTYH	c.452A>G	p.Tyr151Cys	0.0015	MYH-associated polyposis	CHN, AFR, AMR, FIN, NFE_BGR, NFE_NWE, NFE_SEU, NFE_SWE, NFE_ONF, SAS	10
OGG1	c.137G>A	p.Arg46Gln	0.0022	Clear cell carcinoma of kidney	AFR, AMR, ASJ, FIN, NFE_BGR, NFE_NWE, NFE_SEU, NFE_SWE, NFE_ONF, SAS	10
XRCC4	c.25del	p.His9ThrfsTer8	0.0004	Short stature	ICE, AFR, AMR, FIN, NFE_BGR, NFE_NWE, NFE_SEU, NFE_SWE, NFE_ONF, SAS	10
ERCC3	c.325C>T	p.Arg109Ter	0.0005	Unknown	AMR, ASJ, FIN, NFE_BGR, NFE_NWE, NFE_SEU, NFE_SWE, NFE_ONF, SAS	9
MSH6	c.3261dup	p.Phe1088LeufsTer5	0.0001	Lynch syndrome	CHN, ICE, AFR, AMR, FIN, NFE_NWE, NFE_SWE, NFE_ONF, SAS	9
FANCM	c.5101C>T	p.Gln1701Ter	0.0013	Fanconi anemia	ICE, AFR, AMR, FIN, NFE_BGR, NFE_NWE, NFE_SEU, NFE_SWE, NFE_ONF	9