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Researchers See Modest Effects in Individuals With Rare Gene Knockouts

NEW YORK (GenomeWeb) – In a study published in Science today, an international team explored the prevalence and potential consequences of rare, homozygous loss-of-function (rhLOF) mutations in hundreds of human genes.

By sequencing the protein-coding portions of the genome in thousands of adult individuals of British-Pakistani descent, the researchers narrowed in on rare, homozygous mutations predicted to effectively "knock out" almost 800 genes. The apparent health consequences of these mutations were less pronounced than might be expected, they explained, even for many of the individuals with mutations implicated in recessive disease.

Based on their findings, the study's authors cautioned that "apparent rhLOF genotypes identified by exome or genome sequencing from adult populations require cautious interpretation."

"Although this class of variants has the greatest predicted effect on protein function," they continued, "loss of most proteins is relatively harmless to the individual, and even in previously annotated disease genes predicted rare LOF homozygotes may not always be as clinically relevant as often considered."

Sequence data from population studies, such as the 1000 Genomes Project and studies of Icelandic individuals by researchers at the University of Iceland and Decode Genetics, along with efforts such as the Exome Aggregation Consortium, have uncovered a slew of human genes affected by rhLOF mutations, the team noted.

Still, the rarity of these alterations has made it difficult to systematically gauge the consequences of mutations that knock out human genes, even when accompanying phenotypic and/or clinical data are available for members of the populations being studied.

The investigators suspected they might find more instances of the rhLOF glitches by focusing on individuals with longer than usual stretches of homozygous sequences in their genomes, due to parental relatedness.

With that in mind, they did exome sequencing on 3,222 individuals of Pakistani descent who were living in the UK. The group had higher-than-usual rates of parental relatedness, often involving who were first cousins, but the individuals were generally either healthy or receiving treatment for type 2 diabetes or pregnancy.

In the exomes, the team saw 1,111 examples of rare homozygous genotypes that were expected to dramatically alter the resulting protein, leading to a loss of the protein's function.

The alterations, which appeared in 821 of the individuals considered, fell at 847 variant sites in 781 genes. Thousands more rare LOF mutations turned up in the heterozygous context, affecting just one copy of a given gene.

The set of affected genes included more than 200 genes with orthologues that have been assessed in knockout mice, the authors noted, providing clues to deleterious changes in protein interactions that can arise when such genes are missing.

But the researchers did not see consistent ties between knockout-inducing mutations and disease. Instead, data on individuals' visits to the doctor or prescription patterns indicated that 638 individuals with rhLOF mutations were about as likely to access healthcare as the 1,524 controls from the same birth cohort.

In 38 individuals with rhLOF mutations expected to cause recessive disease based on information in the Online Mendelian Inheritance in Man database, meanwhile, the team identified just six individuals whose health records jibed with diseases predicted from their genes.

The researchers also came across a healthy woman carrying mutations that did away with the function of PRDM9, which codes for a protein that mediates meiotic recombination hotspots. Their phased genome data on the woman and her child revealed many examples of recombination occurring outside of PRDM9-related hotspots, despite the lack of obvious health consequences.

"We anticipate that further efforts to identify naturally occurring human knockouts … will yield both new data relevant to clinical interpretation, and new biological insights, as exemplified by our investigation here of a PRDM9-deficient healthy and fertile woman," authors of the study concluded.