A Gutsy Step Forward for Diabetes

Researchers at Columbia University’s Berrie Diabetes center may have found a way to treat people with type 1 diabetes using gastrointestinal (GI) cells. Dr. Accli’s lab has recently replicated a study previously conducted that used diabetic mice treated with genetically engineered GI cells. The study showed by turning off only a single gene, FOX01, GI cells became insulin-producing cells that could almost normalize a diabetic mouse’s glucose levels. The experiment proved successful with humans as well. By turning off FOX01, GI cells proved to be a more feasible option than insulin-producing cells created from embryonic and adult stem cells. This is due to the fact that the converted cells were able to release insulin only as a response to glucose levels. Dr. Accli is hopeful for a drug that can be used to inhibit FOX01 in GI cells to treat diabetics. Article

Turtle Draft-Genomes Yield Insight into Their Body Development and Evolution

The first genome wide phylogenetic analysis of two turtle species tackles the questions about the origin of the turtle’s unique anatomical features. Turtles have a unique exterior shell and skeletal layout that differs from that of their fellow tetrapods. Their carapace is a transformed vertebrae and ribs, their shoulder blades are ventral rather than dorsal, and their skulls lack temporal fenestra. These characteristics led to an analysis of their genome that found that turtles are closely related to Archosauria and that their morphological evolution was the cause of alterations in their signaling cascade. Investigations into their embryonic gene regulation led to the belief that they are morphologically similar to chickens, but have an hourglass-like divergence that shows where exactly (vertebrate phylotypic period) the structure of the shell begins to form.

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Research team unravels genetic mechanism underlying common SNP associated with blond hair in Europeans.

Guenther et al. publish in this week's Nature Genetics on their research demonstrating that a single nucleotide substitution in a transcription factor binding site upstream of the KITLG gene decreases the binding of the LEF1 transcription factor, thereby decreasing expression of the gene by ~20% and contributing to lightened pigmentation of the hair. Many genome wide association studies reveal associations between SNPs and phenotype, but discovering the exact genetic basis of these correlations remains challenging. This study provides a great example of painstaking effort by the research team to identify the causal SNP in a blond-associated haplotype and the necessary experimental validation of its functional impact in human cell lines and transgenic mice. Although this is an impressive achievement, as Hopi Hoekstra writes in a comment piece, it also demonstrates the challenges facing researchers in identifying and characterizing the impact of cis-reulgatory changes.

Also particularly notable about this paper is its citation of the work of YMAL lab member, Susan Walsh!

New Data Further Complicates Human Origins

Mitochondrial (mtRNA) testing of 17 individuals from the Sima de los Huesos, or “Bone Pit” archaeological site has further complicated the current understanding of human evolution. Previously, the site in Burgos, Spain has yielded 6,500 pieces of human skeletons, representing at least 28 individuals. These were classified as Homo heidelbergensis, the name given to the first humans who lived in Europe starting about 600,000 years ago. However, mitochondrial DNA testing found that these individuals had more similarities with another group of proto-humans, the Denisovans. The Denisovans and heidelbergensis were thought to have evolved distinct mtDNA prior to migration. Thus finding Denisovan mtRNA in Spain is contradictory, as they were only found in Asia. In the words of the article, these new findings only prove that "building a coherent story out of [human evolution] is a long-winded business.”

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Genetic Diversity In Mexico

Researchers have shown that there is substantial genetic variation between ethnic groups in Mexico.  Generations of geographic separation have fostered differences between populations, and the data have allowed the authors to come to interesting and medically relevant conclusions.  First, the variation has made it possible to genetically map historical movements between the populations.  Mexican history has, for many Mexican residents, generated a medley of ancestry including indigenous, European and African descent.  Second, understanding this variation and its sources allows doctors to know genetic risks for the relevant populations.  For example, the researchers identified a gene variant that affects lung function, and there are direct diagnostic implications.

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Genome Sequencing Beats Cancer

The time and costs of genome sequencing are getting smaller every year. Within 5 to 10 years, cancer treatments tailored to individuals may be commonplace.

Dr. Lukas Wartman, a leukemia doctor, was diagnosed in 2003 with Acute Lymphoblastic Lymphoma. After his second relapse in 2011, the future seemed grim. As a last resort, his colleagues at Washington University in St. Louis decided to sequence his entire genome, exome, and RNA sequence. The university was able to pool its resources, and it took only a few weeks to extract and analysis his genetic information. After determining through RNA analysis that his FLT3 gene was over-expressed in cancer cells, his doctors prescribed Sutent, a drug made by Pfizer. Two weeks after taking this drug, Dr. Wartman's bone marrow biopsy and flow cytometry came back clean. Dr. Wartman then underwent another bone marrow transplant. As of September 2013, the cancer has not returned.

http://www.nytimes.com/2012/07/08/health/in-gene-sequencing-treatment-for-leukemia-glimpses-of-the-future.html?_r=2&pagewanted=all&

http://genome.wustl.edu/articles/detail/doctor-survives-cancer-he-studies/

Blind mole rat genome sequenced

A new Nature Communications paper examines the comparative genomics of the blind mole rat. Blind mole rats show unusual resistance to cancer, and this study identified some specific protein changes (at gene p53) that might underlie this medically-relevant trait.  Even more interesting -- the study found genomic signatures of adaptations to living underground. For example, changes to circadian rhythm genes (CLOCK) show interesting patterns of convergent evolution with the distantly-related naked mole rat.

Toiletries to aid your microbiome!

From the New York Times Magazine:  "My No-Soap, No-Shampoo, Bacteria-Rich Hygiene Experiment"

The thousands of bacterial species that make up our microbiome provide a "second genome" with an important role in maintaining and promoting human health.  Soaps that kill bacteria on our skin might  in fact be more damaging than hygienic. Arguing that adding specific microbes can promote hygiene and treat skin ailments, a new start-up company, AOBiome, is marketing a body spray (AO+ Refreshing Cosmetic Mist) with ammonia-oxidizing bacteria.   Journalist Julia Scott tried it for a month... and seems unconvinced.

Aotus monogamy

Observations suggest that Azara's Owl Monkey is monogamous, which is rare in the animal kingdom.  they are the first primate to be documented as being monogamous.
**Note: I saw this blurb in the NY Times Science Times a few weeks back and forgot to post it--sorry for the delay!  The NY times blurb and the original paper are linked here:
http://www.nytimes.com/2014/03/25/science/no-monkeying-around-for-these-partners.html?_r=0
http://rspb.royalsocietypublishing.org/content/281/1782/20140195

Correlated evolution of sensory structures and sensory genes in mammals

An article by Garrett & Steiper just published in Proceedings of the Royal Society B looked at anatomical correlates of main olfactory system (ethmoid) and vemoronasal system (vemoronasal organ, VNO) across mammals as well as the size of the related gene families (OR, V1R, and V2R) in mammalian genomes. They found that absolute ethmoid area is correlated with the proportion of functional ORs and that the relative size and complexity of the VNO is correlated with proportion of functional V1R genes in mammalian genomes. These results show nice concordance between anatomical and molecular evolution and may indicate a role for natural selection in the evolution of these genes families.

Genome wide association of methylation with BMI

A recent issue of The Lancet featured an epigenome wide association study (EWAS) of methylated CpGs associated with BMI. Sites were identified in an initial cohort of 479 Europeans and, after filtering data for false positives, inspected in a replication cohort of 339 people. Sites still significant were tested in a larger second replication cohort of 1789 individuals. Five sites were identified as significantly associated with BMI, three of which fall within the first intron of the gene HIF3A, which encodes a subunit of the Hypoxia Inducible Transcription Factor (HIF). Chromatin state at this intron indicates regulatory activity. For all these cases, increasing methylation is linearly correlated with increasing BMI. Notably, the association is tissue specific, manifesting in blood and adipose tissues, but not skin.

Alu elements found to function similarly to enhancers

In a recent issue of Cell authors Su et al. carried out genome-wide analyses of genomic distribution, evolutionary conservation, histone positioning and epigenetic profiles to examine the characteristics of Alu elements. They found that Alu elements in multiple tissues and cell-lines resemble those of putative transcription enhancers. They also find that Alus show long-range interactions with gene promoters, and their similarity to enhancers becomes more prominent with their age in the human genome. The authors conclude that some Alu elements can function as enhancers, and, further, that many more Alus may be proto-enhancers that serve as a repertoire for the de novo birth of enhancers.

A critical period discovered in development of the olfactory bulb

Authors Tsai and Barnea report in the most recent issue of Science that a critical period exists during which an olfactory “sensory map” becomes established. Previous findings show that the olfactory system exhibits enhanced plasticity that is maintained throughout life due to continuous neurogenesis of sensory neurons in the nose and olfactory bulb. However, the authors found evidence in mice that there is less plasticity than originally thought and that a sensory map is created during a developmental critical period. Specifically, the authors were able to test the neural pathways of transgenic mice, finding that perinatal expression of the transgenic odorant receptor (i.e. before the sensory map is established) led to activation of new axons. In contrast, expression of the transgenic receptor after the sensory map was established did not activate new axons.

A review of methods for DNA methylation analysis

Peter Laird, in a 2010 issue of Nat. Rev. Genet., reviews the technology of genome-wide DNA methylation analysis. The review gives the pros and cons of each methodology, as well as the principle behind the analyses. Additionally, he provides information on statistical issues and a list of bioinformatics resources for DNA methylation analysis.

Positive selection of hair, skin and eye pigmentation in Europeans over the last 5000 years

In the current issue of PNAS Wilde et al. find evidence for positive selection of skin, hair and eye pigmentation in Europeans during the last 5000 years. They looked at selection acting on three polymorphic sites that been previously identified in GWAS and fine-mapping SNP association as related to pigmentation in Europeans. They used ancient DNA and computer simulations to estimate the strength of selection on these genes. Their results and analyses indicate that positive selection on pigmentation variants associated with depigmented hair, skin and eyes has been operating within western Eurasia for the past 5000 years. The authors propose two hypotheses for the selection on hair and eye color, in particular. They hypothesize that changes in hair and eye pigment may be byproducts of a selection on skin pigment, or they propose that selection for depigmented eyes and hair may be driven by mate preference.

An In-depth look at gene expression in the developing brain

Miller et al. published a paper in this week's Nature describing the group's study of gene expression in the brain across tissue types during gestational weeks 15-21. RNAs were analyzed from over 300 anatomical regions and in situ hybridization was used to localize expression of elements of interest. Several genes show differential patterns of expression in humans compared with the mouse. Genes nearby human-accelerated noncoding regions show high differential expression among different regions of the neocortex. Notably, FOXP2 expression is enriched in putative language areas. More about the paper's many analyses and findings can be heard on the Nature podcast.

Multigenerational Effects of Stress in a Rat Model

A recent paper in Hormones and Behavior describes a rat model of social stress and its intergenerational effects. The study investigated the effects of stress (exposure to intruding males) on lactating rat mothers on their offspring and offspring's offspring. These stressed mothers groomed and fed their infants less often, and were more aggressive. Upon reaching adulthood and breeding, offspring females (F1) showed a deficit in maternal care, as well as decreased oxytocin, vasopressin, and prolactin gene expression. Their own offspring (F2) demonstrated decreased social activity as juveniles and adults, as well as depressed plasma corticosterone.The authors propose that this system offers a useful model for human anxiety and depression.

Crosstalk between genetic and epigenetic regulation in a model of stem cell regeneration

An article from PNAS earlier this year examines how adult stem cells regulate differentiation, proliferation and apoptosis through crosstalk between genetic and epigenetic regulation.  These three processes are important in organs and tissues to maintain cell populations that undergo stochastic fluctuations and genetic mutations over the course of a lifetime. The authors take a mathematical approach, without considering molecular details, to show how control strategies of these three processes during cell division may be chosen to maximize expected performance. Their model incorporates the performance functions of stem cells at two time scales: the time of one cell cycle and the lifetime of the tissue. Their model includes a feedback regulation that controls proliferation through both the cell population and heterogenous dependence on the epigenetic states, which is different than the typical feedback model that only depends on the size of the cell population. The model accounts for the elimination of genetically mutated cells by depending on apoptosis at each cell cycle. The authors suggest that this apoptosis maximizes the efficiency of stem cell regulation and demonstrates the cross-talk between DNA variants and epigenetics.