Category Archives: Human Genetics

9 hours ago by Heather Zeiger Mitochondria. Credit: Wikipedia commons

(Phys.org)The majority of the human genome is located within the nucleus. However, there is a small but important portion of DNA located within the mitochondria. This mitochondrial DNA (mtDNA) has received much attention in the last few years for tracing ancestry, mitochondrial disease, and three-parent IVF. Mitochondrial DNA's unique properties mean that it has different regulatory mechanisms. A new study by Dmitry Temiakov from Rowan University reports for the first time evidence that mtDNA transcription and replication are regulated by a molecular switch that may provide insight into developmental processes such as embryogenesis and spermatogenesis. The results are reported in Science.

Mitochondrial DNA, unlike nuclear DNA, undergoes transcription and replication at the same location. The transcriptional proteins used to read the mitochondrial RNA (mtRNA) strand, made from the mtDNA, are different from the ones used in replication but occur at the same time and space, which could potentially result in a collision and subsequent problems in gene expression. Temiakov's group investigated whether TEFM, a mitochondrial transcription elongation factor that has been shown to escalate transcription activity in promoterless DNA, plays a role in regulating transcription and replication in the mitochondria.

Transcription in the mitochondria occurs at two locations, the light strand promoter and the heavy strand promoter. Prior studies have shown that transcription terminates early, about 120 base pairs before the light strand promoter, at a region of mtDNA found in most vertebrates, known as CSBII, or conserved sequence block II. A hybrid complex forms with the nascent RNA and the nontemplate strand of DNA.

This complex forms near the origin of the of the replication primer for the heavy strand, and will replicate two-thirds of the mtDNA on the heavy strand. It stops near the origin of the light strand. The now single light strand forms a hairpin structure that is recognized by the mitochondrial RNA polymerase as the signal to begin replication of the light strand.

Temiakov's group showed that in the presence of TEFM, the mitochondrial DNA polymerase does not stop at CSBII as it typically does in human mtDNA transcription, but continues transcribing through the CSBII section. Because TEFM prevents transcription termination, it also prevents the synthesis of the mtDNA polymerase primer that is used in replication. This finding provided one of several clues that TEFM acted to regulate replication and transcription in human mitochondrial DNA.

While conducting this study, the group inadvertently found that because their reference genome has a rare polymorphism in the CSBII region, they observed a decrease in efficiency of the transcription termination mechanism. They believe that the polymorphism disrupted the formation of the G-quadruplex, and that this G-quadruplex is involved in the CSBII mechanism.

Further investigations of how the G-quadruplex is involved in the TEFM mechanism showed that the TEFM interacts with the particular portions of the nascent RNA transcript. Temiakov's group believes that the TEFM interferes with the formation of the G-quadruplex, causing the hairpin structure to not form. This, in turn, does not signal to the mtRNA polymerase to begin replication.

Further studies showed that TEFM affects how well mtRNA polymerase is able to produce long transcripts. Without TEFM, shorter transcripts are formed, terminating at the CSBII region. TEFM increases processivity of mtRNA polymerase.

Temiakov concludes that TEFM serves as a switch that either "turns on" transcription, making it more efficient, or it "turns on" replication. This research indicates that replication and transcription are likely mutually exclusive processes in the human mitochondrial genome precluding the possibility that the transcription and replication processes will collide. Furthermore, this switch may be a key player in the developmental processes in which transcription of mtDNA occurs but not replication.

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Genetic switch regulates transcription and replication in human mitochondria

February 2, 2015

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Brett Smith for redOrbit.com Your Universe Online

Throughout our evolution, viruses have infected an egg or sperm, incorporated themselves into the genetic code and passed on to future generations. While these viruses appear to have no ill effects on us, some of them have been known to cause cancer and other health problems in other mammals.

For geneticists, these endogenous retroviruses (ERVs)serve another function they can reveal details about a species evolution and genetic diversity.

According to a new study published in the journal Retrovirology, humans have far fewer ERVs than other mammals, including close relatives like chimpanzees. The study team said this discrepancy was probably due to humans starting to use tools and weapons in conflicts as opposed to biting and scratching each other like our primate cousins.

Considering us simply as a primate species, the proportion of human individuals that are infected with retroviruses is much less than among our relatives such as chimpanzees, said Robert Belshaw, a genomics professor from Plymouth University in the United Kingdom.

In the study, the scientists analyzed the genetic signature of the two opposite sides of viruses in 40 mammalian species, including humans. These edges are very similar when the virus first incorporates itself into the genome, but as they get random mutations over time, they slowly start to diverge. By monitoring this split, the study team could see how long the retrovirus had been in an animals genome.

Using this gauge, they learned that far fewer retroviruses were included in the genome for humans and other great apes during the last 10 million years compared to other animals. Even compared to animals very similar to us, humans are abnormal in not getting any new kinds of retroviruses in their DNA over the last 30 million years.

Less blood means fewer viruses

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Retroviruses reveal mammalian genetics

Keith Yamamoto, PhD
Keith Yamamoto #39;s talk "Opening Remarks Precision Medicine" at UCSF Informatics Day 2014.

By: UCSF Institute for Human Genetics

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Keith Yamamoto, PhD - Video

Bringing Genetics and Epigenetics to the Fetal-Adult Hemoglobin Switch
Bringing Genetics and Epigenetics to the Fetal-Adult Hemoglobin Switch Air date: Wednesday, January 21, 2015, 3:00:00 PM Category: WALS - Wednesday Afternoon...

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Bringing Genetics and Epigenetics to the Fetal-Adult Hemoglobin Switch - Video

Robert Nussbaum, MD
Robert Nussbaum, MD presents "The Genomic Medicine Initiative at UCSF" at UCSF Informatics Day 2014.

By: UCSF Institute for Human Genetics

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Robert Nussbaum, MD - Video

Michael Blum, MD
Michael Blum, MD presents "Digital Health" at UCSF Informatics Day 2014 conference.

By: UCSF Institute for Human Genetics

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Michael Blum, MD - Video

Sorena Nadaf, MS, MMI
Sorena Nadaf presents "Translational Informatics OnCore Clinical Research and Integration with APeX and iRIS" at UCSF Informatics Day 2014.

By: UCSF Institute for Human Genetics

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Sorena Nadaf, MS, MMI - Video

Sam Hawgood, MBBS
UCSF Chancellor Sam Hawgood presents "Informatics at UCSF" at UCSF Informatics Day.

By: UCSF Institute for Human Genetics

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Sam Hawgood, MBBS - Video

The molecular diagnostics company that had won patents of two human genes that were invalidated by a landmark Supreme Court ruling has decided to abandon separate patent litigation surrounding how scientists study those genes.

The Supreme Court in 2013 struck down Myriad Genetics' patents of the human genes BRCA1 and BRCA2. Mutations of those genes have been linked to a higher risk of breast and ovarian cancer. The patents had given Myriad a monopoly over medical testing of those genes in a bid to detect early signs of cancer, often charging women $3,000 per test or more.

The court's decision opened the door to other companies offering cheaper tests. Myriad sued them, however, claiming that they were infringing on other Myriad patents that the Supreme Court did not invalidate.

But after some unfavorable court rulings, Utah-based Myriad has agreed to withdraw from the litigation. Settlements have included companies like Invitae, LabCorp and Pathway Genomics. More are to follow.

"We decided it was in the best interest of the company to settle these matters, Ronald Rogers, a Myriad spokesman, said.

The legal tussle began in 2009, when the American Civil Liberties Union sued Myriad on behalf of patients, researchers, and others. The civil rights group said that Myriad's patents, awarded more than a decade ago, were so broad that they prevented anybody from testing the genes without Myriad's permission.

The Supreme Court agreed.

"Indeed, Myriads patent descriptions highlight the problem with its claims. For example, a section of the 282patents Detailed Description of the Invention indicates that Myriad found the location of a gene associated withincreased risk of breast cancer and identified mutations of that gene that increase the risk, Justice Clarence Thomas wrote(PDF). He said isolated DNA is a product of nature and not patent eligible.

Sandra Park, a senior staff attorney with the ACLU's Women's Rights Project, said, "it's time for the US Patent Office to strictly enforce the prohibition on patenting products of nature moving forward."

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Patent litigation over human gene breast cancer testing is ending

Josh Denny
Josh Denny, MD presentation "Mining Electronic Health Records to Advance Genomic Discovery" at UCSF Informatics Day 2014.

By: UCSF Institute for Human Genetics

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Josh Denny - Video