A large survey of human genetic variation shows that rare genetic variants are not so rare after all and offers insights into human diseases.
"I knew there would be rare variation but had no idea there would be so much of it," said the senior author of the research, John Novembre, an assistant professor of ecology and evolutionary biology and of bioinformatics at UCLA.
A team of life scientists studied 202 genes in 14,002 people. The human genome contains some 3 billion base pairs; the scientists studied 864,000 of these pairs. While this is only a small part of the genome, the sample size of 14,002 people is one of the largest ever in a sequencing study in humans.
"Our results suggest there are many, many places in the genome where one individual, or a few individuals, have something different," Novembre said. "Overall, it is surprisingly common that there is a rare variant in the population.
"This study doesn’t tell us how to cure a particular disease but suggests that disease in general may be caused by rare variants, and if you’re trying to find the genetic basis of disease, it’s important to focus on those variants. Understanding the genetic basis of disease provides clues to how the diseases work and clues about how to treat them."
The scientists discovered one genetic variant every 17 bases, which was a dramatically higher rate than they expected, said Novembre, a population geneticist who is a member of UCLA’s interdepartmental program in bioinformatics.
"We saw lots of that," he said. "We discovered there are many places in these 202 genes where there is variation and only a few individuals differ from the whole group, or only one differs. We also see evidence that a substantial fraction of these rare genetic variants appear to be deleterious in a long-term evolutionary sense and might impact disease."
The research team included Daniel Wegmann, a former UCLA postdoctoral scholar in Novembre’s laboratory and a co-first author of the study; Darren Kessner, a UCLA graduate student in the bioinformatics interdepartmental Ph.D. program; colleagues from the University of Michigan, Ann Arbor (in fields including human genetics and biostatistics); and geneticists from international health care company GlaxoSmithKline, including project leader Matthew Nelson. The UCLA life scientists were involved in the population genetic analysis of the data.
In the study, 10,621 people had one of 12 diseases, including coronary artery disease, multiple sclerosis, bipolar disorder, schizophrenia, osteoarthritis and Alzheimer’s disease; 3,381 did not have any of the diseases.
"The large sample size allows us to see patterns with more clarity than ever before," Novembre said. "If rare variants are like distant stars, this kind of large sample size is like having the Hubble Telescope; it’s allowing us to see more than before. We see a ton of rare variation, and these rare variants more often make changes to proteins than not. In that way, this study has important implications for the genetic basis of disease in humans. It’s consistent with the idea that many diseases may be partly caused by rare variants."
"The fact that we see so many rare variants is in part due to the fact that human populations have been growing very rapidly," Novembre said. "Because the human population has grown so much, the opportunity for mutations to occur has also grown. Some of the variants we are seeing are very young, dating to population growth since the invention of agriculture and even the Industrial Revolution; this growth has created many opportunities for mutation in the genome because there are so many transmissions of chromosomes from parent to child in large populations."