A survey of loss-of-function variants in the human genome

MacArthur DG, et. al. (2012) "A Systematic Survey of loss-of-Function Variants in Human Protein-Coding Genes." Science: 335.

Loss-of-function (LOF) variants, or alleles that stop protein activity, are expected to be rare for most genes. These authors looked at whole genome data from a pilot of the 1000 genomes project for variants of genes that had some loss of function. They had four categories of interest: 1) nonsense mutations (new stop codons inserted into the gene), 2) site disrupting single-nucleotide variants (SNVs; sites that disrupt exon splicing), 3) indels expected to disrupt the reading frame, and 4) very large deletions that removed most of a genes coding sequence.

They found, not surprisingly, that the allele frequencies of LOF variants were shifted towards rare variants, indicating purifying selection is acting strongly on these variants. They also noted that most of the indels and SNVs were clustered around the 3' end of the gene, indicating that mutations toward the end of a gene were less deleterious, and selection on them was weaker. It would have been interesting to see the AFS of these as a separate category, however. They also noted a slight peak in these types of mutations toward the beginning (5' end) of the gene sequence, which they suggested was due to alternate start codons leading to relaxed selection. Overall, this just indicated that the 'meat' of a gene, the part you don't want to mess up, is usually toward the middle.

Interestingly their list of candidate genes that had LOF variants was highly enriched for chemical sensory genes (e.g. those involved in smell and taste). Since a loss of function of one of these alleles isn't immediately fatal, it makes sense that selection to maintain function in these genes is weaker. They did also find several genes that where in regions that show evidence of positive selection. Several of the olfactory genes appear in these regions, and so does one gene that may be involved in brain lipid formation and another in male fertility. These regions could, of course, be positively selected for some other locus, and these deleterious LOF variants were just dragged along.

The most interesting finding of the article is definitely the number of LOF variants per individual. They estimate that most people have about 100 LOF alleles, most of which are heterozygous. They also point out that since theory predicts we should each only carry about 5 recessive lethal mutations, therefore most of these LOF variants are probably only slightly deleterious.

This article did make me think a bit about how splicing works. Most genes have many exons, which are put together to create the final mRNA that is translated into protein. In some transcripts not all exons are present, however. How many of the possible variants do we see, and what determines if we see them or not? For example, if a gene has 6 exons (the average number of exons on the first C. rubella chromosome is 5.5) then there are 192 possible variants, I'm sure we don't see all of them. What causes this? I'm sure someone knows, maybe Emily can shed some light here.