Using sequencing instruments from multiple vendors, scientists from the University of Utah Health, the University of Washington, PacBio, and elsewhere have developed what they claim is the most comprehensive atlas of genetic change through familial generations. Among other details, their analysis revealed that parts of the human genome change much faster than was previously known. The study is described in a new paper that was published in Nature titled “Human de novo mutation rates from a four-generation pedigree reference.”
As explained in the paper, the researchers used sequences from five short-read and long-read sequencing technologies to phase and assemble “more than 95% of each diploid human genome in a four-generation, twenty-eight-member family.” For the study, they used instruments from Illumina, PacBio, Oxford Nanopore, and Element Biosciences.
The participants in the study are a Utah family that has worked with genetic researchers since the 1980s as part of the Centre d’Etude du Polymorphisme Humain (CEPH 1463) consortium. Four generations of the family have donated their DNA and given consent for it to be analyzed. Researchers have been able to study in-depth how new mutations arise as well as how they are inherited. “A large family with this breadth and depth is an incredibly unique and valuable resource,” said Deborah Neklason, PhD, research associate professor of internal medicine at the University of Utah School of Medicine and an author on the study. “It helps us understand variation and changes to the genome over generations in incredible detail.”
By comparing data from parents’ and children’s genomes, the researchers detected both how often new mutations occurred and how they are passed down. This is important information for understanding human biology because “all of the genetic variation that we see from individual to individual is a result of these mutations,” according to Lynn Jorde, PhD, a professor of human genetics at the University of Utah School of Medicine and a co-author on the Nature paper.
The researchers estimate that each individual inherits nearly 200 new genetic changes that are different from either parent. “We estimate 98–206 [human de novo mutations] per transmission, including 74.5 de novo single-nucleotide variants, 7.4 non-tandem repeat indels, 65.3 de novo indels or structural variants originating from tandem repeats, and 4.4 centromeric DNMs,” they wrote in Nature. Furthermore, “among male individuals, we find 12.4 de novo Y chromosome events per generation.”
They also noted that many of these changes occur in DNA regions that are especially difficult to study. Aaron Quinlan, PhD, study co-author and professor and chair of human genetics at the University of Utah School of Medicine, noted that the combination of advanced sequencing technologies that he and his colleagues used made it possible to study these “previously untouchable” regions. “We saw parts of our genome that are crazy mutable, almost a mutation every generation,” he said. “Other segments of DNA were more stable.”
Furthermore, “this study highlights that a single sequencing technology and a single human genome reference are insufficient to comprehensively estimate mutation rates,” they wrote. In future, the researchers hope to explore whether the genetic rate of change differs from one family to the next. For example, “how generalizable are those findings across families when trying to predict risk for disease or how genomes evolve?” Quinlan said.
The sequencing results are being made freely available to the scientific community.
The post Multi-Platform Sequencing Study of Four Generations Sheds Light on Mutation Rates appeared first on GEN - Genetic Engineering and Biotechnology News.
As explained in the paper, the researchers used sequences from five short-read and long-read sequencing technologies to phase and assemble “more than 95% of each diploid human genome in a four-generation, twenty-eight-member family.” For the study, they used instruments from Illumina, PacBio, Oxford Nanopore, and Element Biosciences.
The participants in the study are a Utah family that has worked with genetic researchers since the 1980s as part of the Centre d’Etude du Polymorphisme Humain (CEPH 1463) consortium. Four generations of the family have donated their DNA and given consent for it to be analyzed. Researchers have been able to study in-depth how new mutations arise as well as how they are inherited. “A large family with this breadth and depth is an incredibly unique and valuable resource,” said Deborah Neklason, PhD, research associate professor of internal medicine at the University of Utah School of Medicine and an author on the study. “It helps us understand variation and changes to the genome over generations in incredible detail.”
By comparing data from parents’ and children’s genomes, the researchers detected both how often new mutations occurred and how they are passed down. This is important information for understanding human biology because “all of the genetic variation that we see from individual to individual is a result of these mutations,” according to Lynn Jorde, PhD, a professor of human genetics at the University of Utah School of Medicine and a co-author on the Nature paper.
The researchers estimate that each individual inherits nearly 200 new genetic changes that are different from either parent. “We estimate 98–206 [human de novo mutations] per transmission, including 74.5 de novo single-nucleotide variants, 7.4 non-tandem repeat indels, 65.3 de novo indels or structural variants originating from tandem repeats, and 4.4 centromeric DNMs,” they wrote in Nature. Furthermore, “among male individuals, we find 12.4 de novo Y chromosome events per generation.”
They also noted that many of these changes occur in DNA regions that are especially difficult to study. Aaron Quinlan, PhD, study co-author and professor and chair of human genetics at the University of Utah School of Medicine, noted that the combination of advanced sequencing technologies that he and his colleagues used made it possible to study these “previously untouchable” regions. “We saw parts of our genome that are crazy mutable, almost a mutation every generation,” he said. “Other segments of DNA were more stable.”
Furthermore, “this study highlights that a single sequencing technology and a single human genome reference are insufficient to comprehensively estimate mutation rates,” they wrote. In future, the researchers hope to explore whether the genetic rate of change differs from one family to the next. For example, “how generalizable are those findings across families when trying to predict risk for disease or how genomes evolve?” Quinlan said.
The sequencing results are being made freely available to the scientific community.
The post Multi-Platform Sequencing Study of Four Generations Sheds Light on Mutation Rates appeared first on GEN - Genetic Engineering and Biotechnology News.