Biology subjects

Bolze, A.

Publications and source records attributed to Bolze, A..

4 recordsLinked to original sources

bioRxiv2020

Revealing variants in SARS-CoV-2 interaction domain of ACE2 and loss of function intolerance through analysis of >200,000 exomes

Lay summaryOur researchers took a look at a sequence of DNA known as the ACE2 gene. This gene is most well known for its role in regulating blood pressure. But in recent times, its drawn a lot of attention from the scientific community because it may also serve as a doorway of sorts, enabling viruses like SARS-CoV-2 to infect cells. Our researchers looked at the ACE2 gene in more than 200,000 people, comparing their exact DNA sequences to see where there are differences among people. Variation in the DNA sequence of a gene is common and is sometimes meaningless. But other times, small changes in the DNA sequence can alter the protein that is made from that gene. In this case the ACE2 gene makes the ACE2 protein, which is what the SARS-CoV-2 virus interacts with. We found a lot of variation between individuals and checked to see if that variation coincided with any traits (i.e., people with variant X tend to have high blood pressure more often than people without variant X). All of the traits we looked at were non-COVID-19-related traits, meaning we havent asked these people anything about COVID-19 yet (this is because these DNA sequences were collected before the pandemic). We found that there are a number of variations observed among people in a specific part of the ACE2 gene. These variations are expected to alter the shape or functionality of a specific part of the ACE2 protein: The part that interacts with the SARS-CoV-2 virus. We dont yet know what the real-life significance of this variation is, but its possible that these variants decrease the proteins ability to interact with the SARS-CoV-2 virus, thus decreasing the persons likelihood of being infected. We can speculate that there will be a spectrum of vulnerability to COVID-19 among people, where some people are more vulnerable than others, and that variants in this part of the ACE2 gene may be one of the reasons. The research we presented here shines a light on this part of the ACE2 gene and may give future researchers a direction to go in as they try to figure out what makes people vulnerable to COVID-19 and similar viruses.

genetics↗

bioRxiv2019

Selective constraints and pathogenicity of mitochondrial DNA variants inferred from a novel database of 196,554 unrelated individuals

High quality population allele frequencies of DNA variants can be used to discover new biology, and study rare disorders. Here, we created a public catalog of mitochondrial DNA variants based on a population of 195,983 individuals. We focused on 3 criteria: (i) the population is not enriched for mitochondrial disorders, or other clinical phenotypes, (ii) all genomes are sequenced and analyzed in the same clinical laboratory, and (iii) both homoplasmic and heteroplasmic variants are reported. We found that 47% of the mitochondrial genome was invariant in this population, including large stretches in the 2 rRNA genes. This information could be used to annotate the mitochondrial genome in future studies. We also showed how to use this resource for the interpretation of pathogenic variants for rare mitochondrial disorders. For example, 42% of variants previously reported to be pathogenic for Leber Hereditary Optic Neuropathy (LHON) should be reclassified.

genetics↗

bioRxiv2019

Population Health Genetic Screening for Tier 1 Inherited Diseases in Northern Nevada: 90% of At-Risk Carriers are Missed

In an unselected population of 23,713 participants who underwent clinical exome sequencing as a part of the Healthy Nevada Project (HNP) in Northern Nevada (Renown Health, Reno, Nevada) from March 15, 2018, to Sept 30, 2018 (Table S1) we find a 1.26% carrier rate for expected pathogenic and likely pathogenic genetic variants in (FH: LDLR, PCSK9, APOB), Hereditary Breast and Ovarian Cancer (HBOC: BRCA1, BRCA2) and Lynch Syndrome (LS: MLH1, MSH2, MSH6, PSM2) with over 90% of carriers undetected under current medical practice. 26% of carriers were found to have advanced disease with 70% first diagnosed before the age of 65. Less than 20% of all carriers had any documented suspicion for inherited genetic disease in the medical record and upon direct follow-up survey under 40% of carriers had family history of relevant disease. A population preventative genetic screening approach for patients under 45 may improve outcomes.\n\nO_TBL View this table:\norg.highwire.dtl.DTLVardef@1eb1896org.highwire.dtl.DTLVardef@19b2a11org.highwire.dtl.DTLVardef@1e6da81org.highwire.dtl.DTLVardef@1138699org.highwire.dtl.DTLVardef@e9c415_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable S1:C_FLOATNO O_TABLECAPTIONDemographic Profile of Healthy Nevada Project Participants.\n\nC_TABLECAPTION C_TBL

genetics↗

bioRxiv2018

Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons

Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here eleven new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that six of eighteen (33%) protein-coding mutations and the two (100%) 5-UTR mutations display incomplete penetrance. Three mutations were identified in 2 independent kindreds, due to a hotspot or a founder effect. Lastly, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.

genetics↗