Fruit fly study uncovers functional significance of gene mutations
associated with autism
Date:
March 15, 2022
Source:
Baylor College of Medicine
Summary:
Researchers applied sophisticated genetic strategies in laboratory
fruit flies to determine the functional consequences of de novo
variants identified in the Simons Simplex Collection (SSC),
which includes approximately 2,600 families affected by autism
spectrum disorder.
Surprisingly, their work also allowed them to uncover a new form
of rare disease due to a gene called GLRA2.
FULL STORY ========================================================================== About 1 in 44 children in the U.S. are diagnosed with autism spectrum
disorder (ASD) by the age of 8, according to the 2018 Centers for Disease Control and Prevention surveillance. How a child's DNA contributes to
the development of ASD has been more of a mystery. Recently, clinicians
and scientists have looked more closely at new, or de novo, DNA changes, meaning they only are present in affected individuals but not in the
parents. Researchers have seen that these changes could be responsible
for about 30% of ASD. However, which de novo variants play a role in
causing ASD remains unknown.
========================================================================== Researchers at Baylor College of Medicine and Texas Children's Hospital
have taken a new approach to looking at de novo ASD genetic variants. In
this multi- institutional study published in the journal Cell Reports,
they applied sophisticated genetic strategies in laboratory fruit flies
to determine the functional consequences of de novo variants identified
in the Simons Simplex Collection (SSC), which includes approximately
2,600 families affected by autism spectrum disorder. Surprisingly,
their work also allowed them to uncover a new form of rare disease due
to a gene called GLRA2.
"ASDs include complex neurodevelopmental conditions with impairments
in social interaction, communication and restricted interests or
repetitive behaviors. In the current study, we initiated our work based
on information from a cohort of ASD patients in the SSC whose genomes
and those of their families had been sequenced," said co-corresponding
author Dr. Shinya Yamamoto, assistant professor of molecular and human
genetics and of neuroscience at Baylor and investigator at the Jan and
Dan Duncan Neurological Research Institute at Texas Children's. "Our
first goal was to identify gene variants associated with ASD that had
a detrimental effect." The team worked with the fruit fly lab model to determine the biological consequences of the ASD-associated variants. They selected 79 ASD variants in 74 genes identified in the SSC and studied
the effect of each ASD-linked gene variant compared to the commonly found
gene sequence (reference) as a control, from three different perspectives.
Co-first author, Dr. Paul Marcogliese, postdoctoral fellow in Dr. Hugo
Bellen's lab, coordinated the effort on knocking out the corresponding fly gene, and examining their biological functions and expression patterns
within the nervous system. They then replaced the fly gene with the
human gene variant identified in patients, or the reference sequence,
and determined how it affected biological functions in the flies.
Working with fruit flies carrying either the reference human gene or
the variant forms, co-first author Dr. Jonathan Andrews, postdoctoral
fellow in Dr.
Michael Wangler's lab at Baylor, was the point person investigating
how these gene variants affected fly behavior. As ASD patients exhibit
patterns of repetitive behavior as well as changes in social interaction,
he evaluated the effect of the patient variants on an array of social
and non-social fly behaviors, such as courtship and grooming. "It's
interesting to see that manipulation of many of these genes also can
cause behavioral changes in the flies," Andrews said. "We found a number
of human genes with ASD variants that altered behavior when expressed
in flies, providing functional evidence that these have functional consequences." The third approach involved overexpressing the genes
of interest in different tissue types in fruit flies. Co-first authors
Samantha Deal and Michael Harnish, two graduate students in Baylor's
Graduate Programs in Developmental Biology and Genetics and Genomics, respectively, working in Dr. Yamamoto's lab, headed these studies. "While
some gene variants may lead to conditions because they produce defective proteins, others may lead to disease because they cause overabundance or aberrant function of a particular protein, which can disrupt biological processes. We investigated whether overexpressing gene variants found
in individuals with ASD might explain the detrimental effect for some
of these genes," Deal said.
========================================================================== Altogether, the team generated more than 300 fly strains in which they conducted functional studies of human gene variants associated with
ASD. Their screen elucidated 30 ASD-linked variants with functional
differences compared to the reference gene, which was about 40% of the
genes for which they were able to perform a comparative functional assay.
"Some of the variants we studied had functional consequences that were moderately or clearly predicted to be disruptive, but other variants were
a surprise. Even the state-of-the-art computational programs couldn't
predict they would have detrimental effects," said Yamamoto. "This
highlights the value of using multiple, complementary approaches to
evaluate the functional consequences of genetic variants associated with
ASD or other conditions in a living animal. Our fruit fly approach is a valuable tool to investigate the biological relevance of gene variants associated with disease." In addition, the wealth of data generated by
the researchers revealed gene variants not previously connected with other neurodevelopmental diseases and uncovered new aspects of the complexity
of genetic diseases.
"GLRA2 was one gene we specifically focused on to follow up," Dr. Ronit
Marom, assistant professor of molecular and human genetics at Baylor and
lead clinician of this work said. "We identified 13 patients, five males
and eight females, carrying rare variants of this X-linked gene that had
not been established as a neurological disease gene before. Furthermore,
males and females carried variants with different types of functional consequences and the spectrum of neurological characteristics among
these 13 patients was different between the two groups. For instance,
many of the boys carried loss of function variants and had ASD, while the
girls did not. They mainly presented with developmental delay as the main characteristic of their condition, and carried gain of function variants."
"The picture that emerges is that ASD may not be one disorder involving
many genes. It may actually be hundreds of genetic disorders, like those
caused by certain GLRA2 variants," said Wangler, assistant professor
of molecular and human genetics at Baylor and co-corresponding author
of the work. "We think that this information is important to physicians
seeing patients with ASD." For a complete list of the contributors to
this work, their affiliations and the financial support for this project,
see the publication.
========================================================================== Story Source: Materials provided by Baylor_College_of_Medicine. Original written by Molly Chiu. Note: Content may be edited for style and length.
========================================================================== Journal Reference:
1. Paul C. Marcogliese, Samantha L. Deal, Jonathan Andrews, J. Michael
Harnish, V. Hemanjani Bhavana, Hillary K. Graves, Sharayu
Jangam, Xi Luo, Ning Liu, Danqing Bei, Yu-Hsin Chao, Brooke
Hull, Pei-Tseng Lee, Hongling Pan, Pradnya Bhadane, Mei-Chu
Huang, Colleen M. Longley, Hsiao-Tuan Chao, Hyung-lok Chung, Nele
A. Haelterman, Oguz Kanca, Sathiya N. Manivannan, Linda Z. Rossetti,
Ryan J. German, Amanda Gerard, Eva Maria Christina Schwaibold,
Sarah Fehr, Renzo Guerrini, Annalisa Vetro, Eleina England,
Chaya N. Murali, Tahsin Stefan Barakat, Marieke F. van Dooren,
Martina Wilke, Marjon van Slegtenhorst, Gaetan Lesca, Isabelle
Sabatier, Nicolas Chatron, Catherine A. Brownstein, Jill A. Madden,
Pankaj B. Agrawal, Boris Keren, Thomas Courtin, Laurence Perrin,
Melanie Brugger, Timo Roser, Steffen Leiz, Frederic Tran Mau-Them,
Julian Delanne, Elena Sukarova-Angelovska, Slavica Trajkova,
Erik Rosenhahn, Vincent Strehlow, Konrad Platzer, Roberto Keller,
Lisa Pavinato, Alfredo Brusco, Jill A.
Rosenfeld, Ronit Marom, Michael F. Wangler, Shinya
Yamamoto. Drosophila functional screening of de novo variants in
autism uncovers damaging variants and facilitates discovery of
rare neurodevelopmental diseases.
Cell Reports, 2022; 38 (11): 110517 DOI:
10.1016/j.celrep.2022.110517 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220315141807.htm
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