Complexity of Animals Depends On Diverse Patterns of Gene Regulation

MedicalResearch.com Interview with:
Colin Sharpe

School of Biology
Institute of Biomolecular and Biomedical Science
School of Biological Sciences
University of Portsmouth
Portsmouth, United Kingdom 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: We have long been fascinated by the question of what underpins the increasing complexity of multicellular animals. In a recent publication we looked at changes to the diversity of the NCoR family corepressors (NCoRs) across the Deuterostomes and found an increase in diversity from sea urchins to humans (1). This is due to gene duplication, an increase in alternative splicing and the encorporation of more protein motifs and domains.

In this study we devised a measure of functional diversity based on these three factors and calculated this value for over 12000 genes involved in transcription in nine species from the nematode worm to humans. Orthologues whose increase in diversity correlated with the increase in complexity of these animals were then selected and we looked for common features and interactions between the selected genes.

We found that proteins that regulate the dynamic organisation of chromatin were significantly enriched within the selection.

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Despite Evolution, Genetic Diseases Persist

MedicalResearch.com Interview with:

Carlos Eduardo G. Amorim PhD Columbia University Department of Systems Biology Irving Cancer Research Center

Dr. Amorim

Carlos Eduardo G. Amorim PhD
Columbia University Department of Systems Biology
Irving Cancer Research Center 

MedicalResearch.com: What is the background for this study?

Response: More generally, we were interested in understanding the determinants of the frequencies of mutations that cause disease in humans.

More specially, we wanted to test if a long-standing theory in population genetics (namely mutation-selection balance) was a good explanation for the observed frequencies of disease mutations in humans.

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Autism Spectrum Disorder Found To Be Highly Heritable

MedicalResearch.com Interview with:

Sven Sandin, PhD Assistant Professor Department of Psychiatry Icahn School of Medicine at Mount Sinai New York, NY 10029

D. Sandin

Sven Sandin, PhD Assistant Professor
Department of Psychiatry
Icahn School of Medicine at Mount Sinai
New York, NY 10029 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: In 2014, we estimated the heritability of autism to be approximately 50%. Motivating us then was the lack of studies in autism heritability using population based and the findings from a twin-study in California finding the heritability to be substantially lower than the 80-90% estimated in previous studies. Since then continued efforts working with the questions on heritability and environmental factors for autism we found differences between different methods and different samples. When we went back to our previous data we found the heritability of autism to be higher than previously estimated. We found that our previous result was due to a methodological artifact where the adjustment for differences in follow-up used in that manuscript underestimated the heritability. Using methods used in other heritability studies the heritability is now estimated to 84%. Importantly, as previously concluded, there is no support for any ‘shared environmental factors’ in the etiology of autism, e.g. environmental factors shared between two siblings.

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Prostate Cancer: Immune Content May Predict Response To Post-Op Radiation

MedicalResearch.com Interview with:

Dr. Shuang George Zhao, MD House Officer, Radiation Oncology University Hospital Ann Arbor, MI 48109-5010

Dr. Zhao

Dr. Shuang George Zhao, MD
House Officer, Radiation Oncology
University Hospital
Ann Arbor, MI 48109

MedicalResearch.com: What is the background for this study?

Response: Targeting cancer through the immune system has been a longstanding goal of cancer research, and with recent advances in immunotherapy, it is now a reality. However, the role of immunotherapy in prostate cancer is still being defined. Sipuleucel-T was the first FDA approved immunotherapy in prostate cancer, and is a personalized cellular therapy that has been shown to prolong survival in patients with metastatic prostate cancer. On the other hand, two recent phase III randomized trials looking at ipilimumab, a CTLA-4 checkpoint inhibitor in metastatic prostate cancer have both been negative for their primary endpoint of OS. Interestingly, there was a PSA response, suggesting that there may be some therapeutic effect in a subset of patients. Therefore, understanding the immune infiltrate is likely critical to selecting patients and therapeutic strategies utilizing the immune system. Unfortunately, it is difficult and laborious to histologically assess immune infiltrate directly. Therefore, we used existing high throughput transcriptomic data with new computational methods in order to more fully characterize the immune landscape of localized prostate cancer.

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Study Opens Door To Reducing Melanoma Risk in Redheads

MedicalResearch.com Interview with:

Rutao Cui, MD/PhD Professor  Vice Chair for Laboratory Administration  Director, Laboratory of Melanoma Biology Department of Pharmacology and Experimental Therapeutics Professor of Dermatology Boston University Boston, Mass 02118

Dr. Cui

Rutao Cui, MD/PhD
Professor
Vice Chair for Laboratory Administration
Director, Laboratory of Melanoma Biology
Department of Pharmacology and Experimental Therapeutics
Professor of Dermatology
Boston University
Boston, Mass 02118


MedicalResearch.com: What is the background for this study?

Response: Red-headed people are making up to 1~2% of the world’s population. They carry “red hair color” variants of MC1R (MC1R-RHC) which are responsible for their characteristic features, including red hair, pale skin, freckles and poor tanning ability.

MC1R-RHC also increases risk of melanoma, the deadliest form of skin cancer. People without red hair but with a single copy of MC1R-RHC also have an increased melanoma risk, who may make more than 50% of the northern European population. It is unknown why redheads are more prone to melanoma, and whether the activity of red hair color variants could be restored for therapeutic benefits.

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Genetic Variants Demonstrate Humans Continue To Evolve Through Natural Selection

MedicalResearch.com Interview with:

Hakhamanesh Mostafavi, MS PhD student Department of Chemical Engineering Columbia University

Mostafavi Hakhamanesh

Hakhamanesh Mostafavi, MS
PhD student
Department of Biological Sciences
Columbia University 

MedicalResearch.com: What is the background for this study?

Response: We know very little about the genetic variants that underlie adaptation in humans. This is in part because we have mostly been limited to methods that search for footprints of ancient selection (that has acted for over thousands to millions of years) in the genomes of present-day humans; so by design are indirect and make strong assumptions about the nature of selection.

These days, thanks to advances in genomic technologies, genetic data for large numbers of people is being collected, mostly for biomedical purposes. Accompanied by information on survival and reproductive success of these individuals, such large datasets provide unprecedented opportunities for more direct ways to study adaptation in humans.

In this work, we introduced an approach to directly observe natural selection ongoing in humans. The approach consists in searching for mutations that change in frequency with the age of the individuals that carry them, and so are associated with survival. We applied it to around 210,000 individuals from two large US and UK datasets.

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Gene Helps Explain Why More Women Than Men Have Alzheimer’s

MedicalResearch.com Interview with:

Arthur W. Toga PhD Provost Professor of Ophthalmology, Neurology, Psychiatry and The Behavioral Sciences, Radiology and Engineering Ghada Irani Chair in Neuroscience Director, USC Mark and Mary Stevens Neuroimaging and informatics institute USC Institute for Neuroimaging and Informatics Keck School of Medicine of USC University of Southern California Los Angeles, CA  90032

Dr. Toga

Arthur W. Toga PhD
Provost Professor of Ophthalmology, Neurology, Psychiatry and The Behavioral Sciences,
Radiology and Engineering
Ghada Irani Chair in Neuroscience
Director, USC Mark and Mary Stevens Neuroimaging and informatics institute
USC Institute for Neuroimaging and Informatics
Keck School of Medicine of USC
University of Southern California
Los Angeles, CA  90032 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The ε4 allele of the Apolipoprotein E (APOE) gene is the main genetic risk factor for late-onset Alzheimer’s disease.  This study reexamines and corrects the sex-dependent risks that white men and women with one copy of the ε4 allele face for developing Alzheimer’s disease using a very large data set of 57,979 North Americans and Europeans from the Global Alzheimer’s Association Interactive Network (GAAIN).

The study results show that these men and women between the ages of 55 and 85 have the same odds of developing Alzheimer’s disease, with the exception that women face significantly higher risks than men between the ages of 65 and 75.  Further, these women showed increased risk over men between the ages of 55 and 70 for mild cognitive impairment (MCI), which is often a transitional phase to dementia.

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Familial Hypercholesterolemia: “Junk” RNA May Facilitate Gene Therapy

MedicalResearch.com Interview with:

Tamer Sallam, MD PhD Assistant Professor of Medicine Co-Director UCLA Center for Lipid Management Lauren B. Leichtman and Arthur E. Levine CDF Investigator Assistant Director, STAR Program Division of Cardiology, Department of Medicine David Geffen School of Medicine at UCLA Los Angeles, California 90095-1679 

Dr. Sallam

Tamer Sallam, MD PhD
Assistant Professor of Medicine
Co-Director UCLA Center for Lipid Management
Lauren B. Leichtman and Arthur E. Levine CDF Investigator
Assistant Director, STAR Program
Division of Cardiology, Department of Medicine
David Geffen School of Medicine at UCLA
Los Angeles, California 90095-1679

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: This study is extension of our previous work published in Nature showing that a gene we named LeXis (Liver expressed LXR induced sequence) plays an important role in controlling cholesterol levels. What is unique about  LeXis is that it belongs to a group of newly recognized mediators known as long noncoding RNAs. These fascinating factors were largely thought to be unimportant and in fact referred to as “junk DNA” prior the human genome project but multiple lines of evidence suggest that they can be critical players in health and in disease.

In this study we tested whether we can use  LeXis “gene therapy”  to lower cholesterol and  heart disease risk. This type of approach is currently approved or in testing for about 80 human diseases.

Our finding was that a single injection of LeXis compared with control significantly  reduced heart disease burden in mouse subjects. Although the effect size was moderate we specifically used a model that mimics a very challenging to treat human condition known as familial hypercholesterolemia..Familial hypercholesterolemia is one of the most common genetic disorders affecting up to 2 million Americans and characterized by 20 fold  fold increase risk of early heart attacks and often suboptimal response to currently available treatments.

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DNA Analysis Identifies Subtype of Pancreatic Cancer With Good Prognosis

MedicalResearch.com Interview with:

Nancy You, MD, MHSc, FACS Department of Surgical Oncology The University of Texas MD Anderson Cancer Center Houston

Dr. You

Nancy You, MD, MHSc, FACS
Department of Surgical Oncology
The University of Texas MD Anderson Cancer Center
Houston 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: This study was motivated by the emerging promise of precision medicine and the emerging evidence that immunotherapy may have phenomenal efficacy in particular molecular subtypes of cancers.  This specific molecular subtype shows deficiency in DNA mismatch repair mechanisms and therefore is thought to be more immunogenic.  DNA mismatch repair deficiency can arise from germline defects such as in the case of patients with Lynch Syndrome, an inherited cancer syndrome, or from epigenetic inactivation DNA mismatch repair genes.

Overall, pancreas cancer has seen limited success with conventional chemotherapy.  In our study, we demonstrated that there is a particular molecular subtype of pancreas cancer that is characterized by defect in DNA mismatch repair genes and by microsatelie instability that has a different prognosis than other pancreas cancers.  This subtype of pancreas cancer is suspected to also respond to immunotherapy.

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16 New Genetic Links To Longevity Discovered

MedicalResearch.com Interview with:

Dr. Zoltán Kutalik, PhD Group Leader Swiss Institute of Bioinformatics

Dr. Kutalik

Dr. Zoltán Kutalik, PhD
Group Leader
Swiss Institute of Bioinformatics
Assistant professor at the Institute of Social and Preventive Medicine

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Why do some of us live longer than others? While the environment in which we live – including our socio-economic status or the food we eat – plays the biggest part, about 20 to 30% of the variation in human lifespan comes down to our genome. Changes in particular locations in our DNA sequence, such as single-nucleotide polymorphisms (SNPs), could therefore hold some of the keys to our longevity. Until now, the most comprehensive studies had found only two hits in the genome.

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