A large-scale genetic analysis reveals that genetic factors that cause autism risk are similar in people of different ancestral backgrounds. By examining the DNA of thousands of people in Latin America, researchers have shown that rare genetic mutations associated with autism occur in the same genes across different populations. The results, published in the journal Natural Medicinepoint to a universal genetic basis for autism and highlight the need for a more inclusive clinical diagnosis.
Over the past decade, researchers have discovered several genetic variants that increase a person’s chance of developing autism. These differences tend to occur in highly conserved genes. A highly conserved gene is a segment of DNA that has remained relatively the same throughout most species’ evolutionary history.
Because these specialized genes carry out basic cellular functions, they are subject to strong natural selection. Any spontaneous changes in them are usually removed over time because they interfere with the natural process. When such abnormal changes occur in humans, they often lead to profound neurodevelopmental changes.
Much of the DNA data used to discover these genes associated with autism is based entirely on people of European ancestry. This lack of global representation leaves a big question about whether the genes associated with autism look different in other parts of the world. It also causes real problems in medical clinics when patients seek genetic counseling. When people of non-European ancestry take genetic tests, they often get inconclusive results simply because their genes don’t show up in common reference sites.
To close this gap, an international team of researchers created Genomics of Autism at the Latin American Ancestries Consortium. Marina Natividad Avila, the researcher who led the study, worked with Joseph D. Buxbaum, director of the Seaver Autism Center for Research and Treatment at Mount Sinai. The team wanted to find out if the genetic risk factors for autism differ according to a person’s ancestry. They focused mainly on Latin American populations, which represent a large group with genetic heritage of Native Americans, Africans and Europeans.
The researchers collected and analyzed genomes from more than 15,000 people across North, Central and South America. The group included about 4,700 people diagnosed with autism, along with their parents and unaffected siblings. By comparing the DNA of children with autism to the DNA of their parents, the team can identify spontaneous mutations.
These spontaneous mutations are recent genetic changes that are present in the child but not present in both parents. To find the genes involved, the team used advanced DNA sequencing techniques that read the genetic code. They focused on the exome, a special part of the genome that provides instructions for building proteins. Although the exome makes up a small fraction of our total DNA, it contains most of the mutations known to cause disease.
The researchers looked closely at rare, spontaneous mutations that change or disrupt the way a protein works. They then compared the rates of these disruptive changes in children with autism versus the rates in children without the condition. Through this statistical analysis, the research team found 35 genes strongly linked to autism within the Latin American group. When they compared these 35 genes to those previously found in European populations, they noticed significant overlap.
The biological pathways affected by the genes remained completely consistent across the two groups. For example, both individuals showed mutations in genes responsible for controlling the way neurons communicate with each other in the brain. They also found disruptions in the genes that control the cytoskeleton, the inner structure of the cell. These findings show that the micro-cellular processes that lead to autism are very similar around the world.
It seems that basic biology applies completely regardless of race. The team also reviewed the mathematical tools used by scientists to measure how safe a gene is. Because these tools were built using European DNA data, the researchers wanted to test their accuracy in a different Latin American group. They found that these tools were consistently very accurate for important genes associated with autism.
This means that a highly conserved genetic mutation has the same biological weight regardless of an individual’s ancestry. Finally, the genetic changes that drive the risk of autism were not limited to a single set of ancestors. “Our results show that the basic genetic architecture of autism is shared across generations,” said Buxbaum. “This suggests that the biology behind autism is ubiquitous and underscores the importance of ensuring that diverse populations are represented in genetic research.”
Despite these apparent biological similarities, the researchers noted a few important limitations in their work. When the team used standard medical software to interpret the changes they found, the software marked fewer of them as dangerous in Latin Americans compared to Europeans. In medical genetics, a clearly deleterious mutation is known as a pathogenic variant. This difference in diagnosis occurs because current medical equipment relies heavily on past data, which is heavily biased towards European genetics.
As a result, non-Europeans can still get clear answers from standard genetic tests. Additionally, the study relied on sequencing the protein-coding regions of the genome, rather than the entire DNA sequence. This method makes it difficult to map exactly where a particular gene originated. In highly admixed populations, tracing the exact origin of a small segment of DNA requires complete genome data.
Unmapped mutations in the DNA of less-studied individuals may also mask certain genetic risk factors. To correct these medical blind spots, researchers must continue to sequence the DNA of various people around the world. Adding non-European genes to medical databases will help improve the tools used to diagnose neurodevelopmental conditions. As these data centers grow, doctors will be able to provide better, more accurate genetic counseling to families of all backgrounds.
These future efforts will help ensure that the benefits of appropriate medicine reach everyone. Medical experiments must come to terms with the fact that human biology has a common foundation. “These findings provide a roadmap for improving genetic analysis in ancestral populations,” Buxbaum added. “Increasing genomic research in disadvantaged populations is critical to reducing health disparities and advancing appropriate medicine for autism and related conditions in all populations.”
The study, “Deleterious coding variation associated with autism is shared across generations,” was written by Marina Natividad Avila, Seulgi Jung, F. Kyle Satterstrom, Jack M. Fu, Tess Levy, Laura G. Sloofman, Lambertus Klei, Thariana Pichardo, Dalia Marquez, Christine Carolsi Ameine RS Campos, Hilda Cerros, Roberto Chaskel, Claudia IS Costa, Michael L. Cuccaro, Andrea del Pilar Lopez, Magdalena Fernandez, Eugenio Ferro, Liliana Galeano, Ana Cristina DES Girardi, Anthony J. Griswold, Luis C. Hernaúndez, Naila Lourenñez, Diana Luurenñez, Diana Luurençnao-Roos Oyama, Katherine P. Peña, Isaac Pessah, Rebecca Schmidt, Holly M. Sweeney, Lizbeth Tolentino, Jaqueline YT Wang, Lilia Albores-Gallo, Lisa A. Croen, Carlos S. Cruz-Fuentes, Irva Hertz-Picciotto, Alexander Kolevzon, Maria Claudia Latti Mayog, Maria Claudia Latti Margaret A. Pericak-Vance, Paige M. Siper, Flora Tassone, M. Pilar Trelles, GALA Consortium, The Autism Sequencing Consortium (ASC), Michael E. Talkowski, Mark J. Daly, Behrang Mahjani, Silvia De Rubeis, Edwin H. Cooker, Kathryna D. Buxbaum.
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