The genomic architecture of inherited DNA variants

Graciela Gutierrez


Houston, TX -

You have your mother鈥檚 eyes and your father鈥檚 smile, but genetics is much more than just what鈥檚 on the surface. In a study that spans more than a decade, researchers at 香港6合开奖结果 have looked at generations of families in a specific population to reveal the role newly inherited DNA variants play on recessive disease traits, and in the process, they have created a population specific database revealing unique DNA information unseen in larger cohorts.

The findings, now published in , revealed a correlation between occurrences of complex genetic disorders in those families with increased levels of consanguinity when compared to unaffected populations. Consanguinity is when both parents contribute similar genetic markers to an offspring, such as by sharing a common ancestor, and the genetic information from both the genome inherited from the father and that from the mother are identical.

鈥淲e observed that the areas on the chromosome known as ROH, regions of homozygosity, were longer in those individuals in which there was a higher degree of parental consanguinity when compared to those with less,鈥 said Dr. Zeynep Coban-Akdemir, postdoctoral associate in molecular and human genetics at Baylor and currently assistant professor at UTHealth School of Public Health as well as co-lead author on the study. 鈥淲e can see what is happening when consanguinity is at play and also when new genetic variations are introduced into the family unit of the clan or tribe representing more distant ancestors.鈥

Dr. Xiaofei Song, a former Baylor graduate student now working as an assistant professor at Moffitt Cancer Center, said, 鈥淲e further applied a statistical method to systematically assess the impact of these genetic variations on disease. Our results indicate that the newly introduced genetic variations can better explain the clinical features observed in our patients.鈥 Song also is co-lead author on the study.

鈥淭he published study contributes to the field of both rare disease and population genomics. From a trainee perspective, the article provides a valuable resource for comprehending fundamental concepts of human genetics and applying diverse computational methods to elucidate these concepts,鈥 said Ph.D candidate Tugce Bozkurt-Yozgatli, with the Acibadem University in Istanbul, Turkey.

Coban-Akdemir, who worked in the Lupski Lab at Baylor 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 that is known to have different variations in genetic markers when compared to other populations from greater Europe. Researchers created and analyzed a database of variants derived from exome sequencing, a genomics assay providing a glimpse into genetic variation genomewide, of 773 unrelated volunteers who were affected with various suspected rare Mendelian disease traits, which are diseases caused by a mutation in a single gene and clearly passed down from one generation to the next in accordance with Gregor Mendel expectations. They were compared to another database created by the same researchers of 643 unaffected relatives.

Roughly half of the genetic variants in this Turkish group are not present in greater European control populations that are found in shared databases commonly used by genetic researchers.

鈥淭his group of Turkish individuals and families gives us insight into genetics that the average population doesn鈥檛 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 they have an enriched genetic variation that is only seen within this population when compared to European populations,鈥 Coban-Akdemir said.  

Dr. Davut Pehlivan, assistant professor of pediatrics 鈥 neurology at Baylor, said on a single individual there are around 40 million Watson-Crick base pair variations within our DNA.

鈥淭he Human Genome Project opened the doors for researchers to investigate entire genomic DNA complement using next-generation sequencing technology. However, more struggles appeared with these advancements. For example, it is hard to pinpoint which variant is causing disease among 40 million variations of our DNA. Studying healthy populations helps us to eliminate many of these common variations from consideration. Thus, we studied both patients and their healthy relatives in the Turkish population.鈥 Pehlivan said. 鈥淭here are a lot of changes in the genome, and we don鈥檛 fully understand the meaning of all of those details, but the data from this population study will help all investigators around the world who are trying to interpret the results of other variants in the human genome DNA.鈥

Pehlivan described gathering the information and families wanting to participate in genomics research beginning in 2010, traveling long distances to rural areas where the patients were mostly located, a human interest story itself, to make sure the database and clinical information would show an accurate representation for these families.

鈥淲e discovered more than 200 genes that contributed to the existing body of disease gene associations. This will help us get closer to understanding, in this population and in others, what is causing these diseases and the human biological perturbation underlying a broad scope of diseases. Our studies will open new avenues of research in human biology and genome biology and eventually help to potentially bring nucleic acid treatments, something used to develop the COVID vaccine, to the patients and families鈥 Pehlivan said.  

鈥淭his team of researchers is not just helping the population that they studied, but their findings also can be applied to many populations. We all are very different individuals on this planet, yet our genes act very similarly, and we all share a common humanity. So, understanding how genetic disorders work helps us to support affected families across the globe,鈥 said Dr. James R. Lupski, the Cullen Foundation Endowed Chair in Genetics and Genomics at Baylor.

In the past, Coban-Akdemir and Dr. Claudia M.B Carvalho, previously with Baylor and currently in her own laboratory at the Pacific Northwest Research Institute (PNRI) in Seattle who also contributed to this study, have worked on studying variants of genes to identify causes of diseases through production of truncated or altered proteins that take on a new or different function. Their work also focused on databases of populations with and without genetic disease. Their current work reflects the importance of diversity and inclusion as work continues to reveal causes of genetic diseases.

This work was supported in part by the U.S. National Human Genome Research Institute /National Heart Lung and Blood Institute grant number UM1HG006542 to the Baylor Hopkins Center for Mendelian Genomics (BHCMG), the U.S. National Human Genome Research Institute U01HG011758 to the 香港6合开奖结果 for the Genomics Research to Elucidate the Genetics of Rare Disease consortium (BCM-GREGoR), the National Institute of Neurological Disorders and Stroke Q22 (NINDS) R35NS105078, and the National Human Genome Research Institute U54-HG003273. J.E.P. was supported by NHGRI K08 HG008986.

Other authors who contributed to the study include: Francisco C. Ceballos, Ender Karaca, Yavuz Bayram, Tadahiro Mitani, Tomasz Gambin, Tugce Bozkurt-Yozgatli, Shalini N. Jhangiani, Donna M. Muzny, Richard A. Lewis, Pengfei Liu, Eric Boerwinkle, Ada Hamosh, Richard A. Gibbs, V. Reid Sutton, Nara Sobreira, Claudia M.B. Carvalho, Chad A. Shaw, Jennifer E. Posey, David Valle. They are affiliated with the Department of Molecular and Human Genetics, 香港6合开奖结果; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, the University of Texas Health Science Center at Houston; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute; Instituto de Salud Carlos III, National Center of Microbiology, Madrid, Spain; Section of Neurology, Department of Pediatrics, 香港6合开奖结果; Sanford Medical Genetics Laboratory, Sanford Imagenetics; Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania; Institute of Computer Science, Warsaw University of Technology; Department of Biostatistics and Bioinformatics, Institute of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey; Human Genome Sequencing Center, 香港6合开奖结果; Department of Pediatrics, 香港6合开奖结果; Department of Ophthalmology, Cullen Eye Institute, 香港6合开奖结果; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine; Texas Children鈥檚 Hospital; Pacific Northwest Research Institute; Baylor Genetics. To view list, along with author contributions, conflicts of interest and ethics declarations, click .

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