Scientists were surprised to find so many of these variants in healthy individuals because loss of gene function leads to diseases such as cystic fibrosis and muscular dystrophy. The findings will allow researchers to better pinpoint new disease-causing mutations by helping them differentiate between frequently occurring but harmless genetic variants and dangerous ones, the authors say.
The study is the latest coming from the 1000 Genome Project, a massive personal genomics push to provide a comprehensive resource on human genetic variation. The international effort is designed to offer a catalogue of human genetic variation that will speed the day when patients will receive personalized care based on their genetic makeup.
The team analyzed the genomes of 185 individuals from Europe, Asia, and Africa, looking for so-called loss-of-function variants in which mutations disable a gene’s ability to make proteins.
“Even though previous studies have shown that loss-of-function variants exist in the general population, their extent has been underappreciated. This is the first time we have a definite sense of variation in the numbers of functional genes between individuals,” said Suganthi Balasubramanian of Yale and lead author in the paper.
The study shows no individual has a full complement of functional genes. On average, each individual has 20 genes where both copies of the gene are disabled.
“In total, this study identified 253 such genes. This means, at least one percent of human genes can be shut down without causing serious disease,” explains Mark Gerstein, the Albert L. Williams Professor of Biomedical Informatics and co-senior author of the paper.
The catalogue of loss-of-function variants in healthy genomes will be invaluable to clinicians as they begin to use personalized genomic analysis to help diagnose and treat disease, the authors say.
“We provide a list of over 1000 loss-of-function variants, and in most cases little or nothing is known about how these genes work or what they do,” said Chris Tyler-Smith, co-senior author from the Wellcome Trust Sanger Institute. “By studying the people carrying them in detail, we should get new insights into the function of many poorly-known human genes.”
The study also showed that as many as a quarter of these variants involve large stretches of DNA called structural variants, rather than mutations of single base-pairs, which were believed to be the primary source of genetic variation. Structural variants are not yet well characterized in the human population and their identification represents a major contribution to the 1000 Genomes Project. The Yale team is also looking at variants outside of regions of DNA that code for genes, an area that constitutes the vast majority of the genome.