The spectrum of rare variation in humans
Through interrogation of the gnomAD database (Karczewski, 2019) of
publicly available exome and whole genome sequence, the number of
synonymous (SYN), non-synonymous (NS), and loss-of-function (LOF)
variants were tabulated (Figure 1, Supplemental Table 2 ). In
addition, we determined the number of individuals homozygous for LOF
variants and adjusted for gene size. The frequency of NS and LOF
variants varies widely by gene. Therefore, this data can provide
information on how essential a gene is by lower-than-expected levels of
LOF mutations, rate of LOF variants per gene, and the ratio of NS/SYN
variants. As expected, the essential, X-linked genes (ABCD1 ,ABCB7 ) and the essential ABCA3 and ABCE1 genes all
have no or a deficient level of LOF variants and a low to very low ratio
of NS/SYN variants.
Interestingly the ABCA2 , ABCB1 , ABCC5 , andABCG1 also have low levels of LOF variants, suggesting that they
do not tolerate loss-of-function. Genes with a higher rate of NS and LOF
variants include ABCC7/CFTR and ABCG2 . Several groups have
proposed a heterozygous advantage for LOF alleles of CFTR to account for
the high frequency of cystic fibrosis mutations in multiple populations
(Angelicheva et al., 1994; Bosch et al., 2017; Prince, 1998).
Furthermore, the increased blood uric acid levels in ABCG2 mutant
carriers may also have a selective advantage against infectious
diseases.
Analysis of specific predicted LOF mutations showed that all the
cytoplasmic ABC genes (ABCE1 , ABCF1 , ABCF2 , andABCF3 ) have no reported homozygotes for LOF mutations, suggesting
that they are essential. Similarly, almost all the half transporters
(except for ABCB6 and ABCG2 ) also have no homozygous LOF
individuals (Supplemental Table 2 ). In contrast,
nearly half (46%) of all ABC full-transporters have at least 1 LOF
allele reported to be homozygous in at least one individual
(Figure 2 ). Interestingly some predicted LOF variants are
frequent, including in some specific populations. For example, several
genes in the ABCA5 gene cluster (ABCA6 , ABCA8 ,ABCA10 ) have common LOF alleles in Latin American and African
populations. ABCA7 , ABCA13 , ABCB5 , ABCC11 ,
and ABCC12 also have specific common predicted LOF variants. Some
of the predicted LOF alleles are in splice sites, and it may be that
they can produce a functional protein by alternative splicing.