You have your mother’s eyes and your father’s smile, but there is much more to genetics than what is on the surface. In a study spanning more than a decade, Baylor College of Medicine researchers looked at generations of families in a specific population to reveal the role that newly inherited DNA variants play in recessive disease traits and, in the process, They created a population. Specific database that reveals unique DNA information not seen in larger cohorts.
The findings, now published in Genetics in Medicine OPEN, revealed a correlation between the emergence of complex genetic disorders in those families with higher levels of consanguinity compared to unaffected populations. Consanguinity is when both parents provide similar genetic markers to an offspring, for example, by sharing a common ancestor, and the genetic information of both the genome inherited from the father and the mother is identical.
“We observed that areas of the chromosome known as ROH, regions of homozygosity, were longer in those individuals in whom there was a greater degree of parental inbreeding compared to those who had less,” said Dr. Zeynep Coban-Akdemir, associate postdoctoral. in molecular and human genetics at Baylor and currently an assistant professor at the UTHealth School of Public Health, as well as co-senior author of the study. “We can see what happens when inbreeding is at play and also when new genetic variations are introduced into the clan or tribe family unit that represents more distant ancestors.”
Dr. Xiaofei Song, a former Baylor graduate student who now works as an assistant professor at Moffitt Cancer Center, said, “We further applied a statistical method to systematically evaluate the impact of these genetic variations on diseases. Our results indicate that “The recently introduced genetic variations may better explain the clinical features observed in our patients.” Song is also co-lead author of the study.
“The published study contributes to the field of rare diseases and population genomics. From the student’s perspective, the article provides a valuable resource for understanding fundamental concepts of human genetics and applying various computational methods to elucidate these concepts,” said the PhD candidate. Tugce Bozkurt-Yozgatli, from Acibadem University in Istanbul, Türkiye.
Coban-Akdemir, who worked in Baylor’s Lupski lab, where the research was conducted, says this is an important part of the findings because it reveals how genes act within different populations and clans to contribute to different recessive genetic disorders.
The population studied was a cohort of individuals originating from Turkey who are known to have different variations in genetic markers compared to other populations in greater Europe. The researchers created and analyzed a database of variants derived from exome sequencing, a genomic assay that provides insight into genetic variation across the genome, from 773 unrelated volunteers who were affected by several rare traits suspected of the disease. Mendelian disease, which are diseases caused by a mutation in a single gene. and clearly passed down from generation to generation according to the expectations of Gregor Mendel. They were compared with another database created by the same researchers of 643 unaffected relatives.
About half of the genetic variants in this Turkish group are not present in the larger European control populations found in shared databases commonly used by genetic researchers.
“This group of Turkish individuals and families gives us insight into genetics that the average population does not provide. What we found in this Turkish population is very unique. Not only is this group underrepresented in larger databases, but it shows us that have enriched genetic variation that is only seen within this population compared to European populations,” Coban-Akdemir said.
Dr. Davut Pehlivan, assistant professor of pediatrics and neurology at Baylor, said that in a single individual there are about 40 million Watson-Crick base pair variations within our DNA.
“The Human Genome Project opened the doors for researchers to investigate the full complement of genomic DNA using next-generation sequencing technology. However, further difficulties arose with these advances. For example, it is difficult to determine which variant is causing the disease among 40 million variations of “Our DNA. Studying healthy populations helps us eliminate many of these common variations from consideration. Therefore, we study both patients and their healthy relatives in the Turkish population,” said Pehlivan. “There are many changes in the genome and we do not fully understand the meaning of all those details, but the data from this population study will help to all the researchers around the world who are trying to interpret the results of other variants. in the DNA of the human genome.”
Pehlivan described collecting information and families who wanted to participate in genomic research beginning in 2010, traveling long distances to rural areas where patients were primarily located, a human interest story in itself, to ensure that the basis of Data and clinical information will show an accurate representation of these families.
“We discovered more than 200 genes that contributed to the existing set of disease gene associations. This will help us get closer to understanding, in this population and others, what is causing these diseases and the human biological disruption underlying a wide range of “Our studies will open new avenues of research in human biology and genome biology and will eventually help bring nucleic acid treatments to patients and their families, something that was used to develop the COVID vaccine,” Pehlivan said.
“Not only is this team of researchers helping the population they studied, but their findings can also be applied to many populations. We are all very different individuals on this planet, yet our genes act very similarly and we all share a common humanity.” “Therefore, understanding how genetic disorders work helps us support affected families around the world,” said Dr. James R. Lupski, Cullen Foundation Professor of Genetics and Genomics at Baylor.
In the past, Coban-Akdemir and Dr. Claudia MB Carvalho, formerly at Baylor and currently in her own lab at the Pacific Northwest Research Institute (PNRI) in Seattle, who also contributed to this study, worked on the study of gene variants to identify causes of diseases by producing truncated or altered proteins that assume a new or different function. His work also focused on databases of populations with and without genetic diseases. Her current work reflects the importance of diversity and inclusion as work continues to reveal the causes of genetic diseases.
This work was supported in part by grant number UM1HG006542 from the US National Human Genome Research Institute/National Heart, Lung, and Blood Institute to the Baylor Hopkins Center for Mendelian Genomics (BHCMG), the National Institute U01HG011758 U01HG011758 to Baylor College of Medicine for the Genomic Research to Elucidate the Genetics of Rare Diseases (BCM-GREGoR) consortium, National Institute of Neurological Disorders and Stroke Q22 (NINDS) R35NS105078 and National Human Genome Research Institute U54-HG003273. The JEP was supported by NHGRI K08 HG008986.