Origins of mutation
Computational analysis reveals sources of genetic variations

Date:
August 13, 2021
Source:
Harvard Medical School
Summary:
The precise transmission of genetic information from one generation
to the next is fundamental to life. Most of the time, this process
unfolds with remarkable accuracy, but when it goes awry, mutations
can arise-- some of them beneficial, some of them inconsequential,
and some of them causing malfunction and disease.



FULL STORY ==========================================================================
The precise transmission of genetic information from one generation to
the next is fundamental to life.


==========================================================================
Most of the time, this process unfolds with remarkable accuracy, but
when it goes awry, mutations can arise -- some of them beneficial, some
of them inconsequential, and some of them causing malfunction and disease.

Yet, precisely where and how heritable genetic mutations tend to arise
in humans has remained largely unknown.

Now, a new multi-institutional study led by investigators at Harvard
Medical School and Brigham and Women's Hospital has pinpointed nine
processes during which most human genetic mutations tend to arise.

The work, published Aug. 12 in Science,is based on an analysis of
400 million rare DNA human variants and represents one of the most comprehensive computational efforts to explore heritable genomic
variations.

"Genetic mutations are a rare yet inevitable and, indeed essential,
part of the development and propagation of the human species -- they
create genetic diversity, fuel evolution, and occasionally cause genetic diseases," said study lead investigator Shamil Sunyaev, professor of
biomedical informatics in the Blavatnik Institute at HMS and professor
of medicine at Brigham and Women's.

"Harnessing the power of computation and big data, we analyzed genomic variations and identified a set of biologic processes responsible for the
vast majority of heritable human mutations," added Sunyaev, who conducted
the work with lead authors Vladimir Seplyarskiy, HMS research fellow
in medicine at Brigham and Women's, and Ruslan Soldatov, instructor in biomedical informatics at HMS.

Key findings The research identified new mutation-fueling mechanisms and
some that were already known. One mechanism was related to inaccurate
copying of DNA, another was related to chemical damage occurring to
the DNA. The analysis also pinpointed a machinery involved in human
gene regulation as a frequent culprit in mutations. This machinery is particularly active during early embryonic development, and most of
the mutations introduced by the machinery occur during this period. In
one surprising finding, the researchers identified a mutation- driving mechanism that was not related to DNA copying and cellular division - - processes that are prone to mutation-causing glitches. This previously unsuspected mechanism leads to mutations in egg cells stored in the
ovaries.

Relevance and implications The researchers are now working to incorporate
some of the results in a model of human-mutation rate along the genome
in an effort to help predict the chance that a specific mutation would
occur at a specific location in the genome. The goal is to help in the
analysis of disease mutations and in discovery of genes causing rare
diseases. The model may also serve to highlight genes of key importance
to human health and survival.

========================================================================== Story Source: Materials provided by Harvard_Medical_School. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Vladimir B. Seplyarskiy, Ruslan A. Soldatov, Evan Koch, Ryan
J. McGinty,
Jakob M. Goldmann, Ryan D. Hernandez, Kathleen Barnes, Adolfo
Correa, Esteban G. Burchard, Patrick T. Ellinor, Stephen
T. McGarvey, Braxton D.

Mitchell, Ramachandran S. Vasan, Susan Redline, Edwin Silverman,
Scott T.

Weiss, Donna K. Arnett, John Blangero, Eric Boerwinkle, Jiang He,
Courtney Montgomery, D.C. Rao, Jerome I. Rotter, Kent D. Taylor,
Jennifer A Brody, Yii-Der Ida Chen, Lisa de las Fuentes, Chii-Min
Hwu, Stephen S.

Rich, Ani W. Manichaikul, Josyf C. Mychaleckyj, Nicholette
D. Palmer, Jennifer A. Smith, Sharon L.R. Kardia, Patricia
A. Peyser, Lawrence F.

Bielak, Timothy D. O'Connor, Leslie S. Emery, Christian Gilissen,
Wendy S. W. Wong, Peter V. Kharchenko, Shamil Sunyaev. Population
sequencing data reveal a compendium of mutational processes in
the human germ line.

Science, 2021; eaba7408 DOI: 10.1126/science.aba7408 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210813100335.htm

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