Monday, September 30, 2013

Mary-Claire King: interviewed in recent PLoS Genetics & portrayed in upcoming independent film

Evidence Is Evidence: An Interview with Mary-Claire King
Dr. Mary-Claire King, of King & Wilson 1975- and BRCA-fame, reflects on her career in this interview.

Decoding Annie Paker 
This new independent film chronicles the discovery of BRCA1 & 2 and features Helen Hunt as Dr. Mary-Claire King.

Forces Shaping the Fastest Evolving Regions in the Human Genome

This article goes into further depth into the subject of HARs brought up briefly in the Bradley review article for this week. HARs, or Human Accelerated Regions, are regions of the genome that are highly conserved in all vertebrates but are found to be rapidly accelerated in humans. While some of these regions have been directly tied to human traits such as neocortical development (HAR1), the majority of them occur in non-coding regions of the genome. This supports the idea in the King & Wilson paper of 1975 that most of human uniqueness comes from the regulation of gene expression in non-coding regions of the genome. This paper focuses on 202 Human Accelerated Regions that are located in intergenic regions and are believed to play important roles in gene expression, with a special focus on evolutionary forces that shaped the selective pressures on these regions. The nature of the HARs in the paper reveal a selective force for the increase of guanine and cytosine bases as well as a tendency for them to occur near transcription genes.


Human and Non-Human Evolutionary Relationships: The Use of iPSC-Derived Neurons

This article published in Biological Psychiatry discusses a new technique to analyze phenotypic differences between humans and other non-human primates/hominids. For the purpose of studying human brain evolution and potential evolutionary links between humans and non-human primates, the researchers made use of induced pluripotent stem cells (iPSC). iPSCs are responsible for the formation of neocortical pyramidal neurons--which lead to species-specific phenotypes. These special category of neurons display morphological variations across various cortical layers in the brain, and are known to be species-specific. Therefore, neocortical pyramidal neurons may offer a unique neurological approach to test evolutionary hypotheses involving humans and non-human primates. This review article also underscores that the morphology of pyramidal neurons is impaired in neurological and psychiatric disorders; due to this characteristic, iPSCs may contribute insights towards to both human medicine and evolutionary relationships. Exciting!

-Neil Pathak

The last common ancestor of humans and chimps probably wasn’t much like either

For a long time, scientists have thought that the common ancestor of humans and chimps would be a chimp-like creature.  Comparisons between humans, chimps, and the other apes led to this conclusion as humans seemed to be the least similar and chimps appeared to share many traits with our relatives like gorillas.  Recent work in paleontology, behavioral biology, and molecular biology has suggested that this assumption may be incorrect.  Studies of the chimp genome have shown that chimps appear to have more genes that have been influenced by natural selection than humans do, suggesting more changes from our common ancestor.  Researchers looking at animal behavior also made a family tree of traits belonging to apes and monkeys and found that our common ancestor likely had a lifestyle pattern different from both humans and chimps today.  Finally, studies on the Ardipithecus ramidus fossil unearthed in 2009 have revealed more potential differences.  The specimen is one of the closest ever found to the chimp-human split, and researchers believe it may have walked on tree branches on all fours like a monkey rather than hung from them like apes.  This conclusion however is still controversial, but when combined with the other studies mentioned here, does point out that chimps have not stayed the same since their split with humans.  Rather, they evolved and changed just as humans did.  

African Ape Demographic History Using Whole Genome Sequences

Hara et al.'s (2012) paper represents the latest study of population history in the Gorilla-Chimpanzee-Human lineage. Thanks to the recent sequencing of the gorilla and orangutan genomes (Locke et al., 2011; Scally et al., 2012) in addition to the chimp and human, Hara et al. were able to utilize whole genome sequences in a Bayesian MCMC framework developed by Rannala & Yang (2003). This paper is nice because they first perform a simulation study to estimate the optimal, recombination-free size block of genome to use. By also paying extra attention to orthology, Hara et al. undertake a robust inference based on many, many independently evolving loci throughout the genome and ultimately estimate the following divergence dates and ancestral effective population sizes:
·      6.0–7.6 Ma human lineage split from chimpanzee lineage with Ne of 75,600
·      7.6–9.7 Ma human + chimpanzee lineage split from gorilla lineage with Ne of 65,500
·      15–19 Ma African ape lineage split from orangutan lineage with Ne of 203,000
Interestingly, Hara et al. also report variation in mutation rates among lineages and chromosomes. This evidence refutes prior claims of ongoing hybridization between humans and chimpanzees after their lineages’ initial split, based on the younger divergence date of the X chromosome (Patterson et al., 2006).


Hara, Y. et al (2012). Reconstructing the Demographic History of the Human Lineage Using Whole-Genome Sequences from Human and Three Great Apes. Genome Biol Evol 4(11):1133-1145. 

Locke, D et al (2011). Comparative and demographic analysis of orang-utan genomes. Nature 269: 529-533. 

Patterson, N et al (2006). Genetic evidence for complex speciation of humans and chimpanzees. Nature 441: 1103-1108.

Rannala, B & Yang, Z (2003). Bayes estimation of species divergence times and ancestral population sizes using DNA sequences from multiple loci. Genetics 164: 1645-1656.

Scally, C et al (2012). Insights into hominid evolution from the gorilla genome sequence. Nature 483: 169-175. 

Wednesday, September 25, 2013

Recently in Science!

This article is a cool conservation biology news piece that details the resurgence of large predator populations in North America.  HERE

An interesting letter calling for geographic information to be attached to GenBank genetic data. HERE

This policy paper looks at ethical questions that will have to be considered in the debate about whether to sequence babies' genomes at birth.  HERE

This paper describes some of the recent questions in the field of biogeography, describing how researchers are working to describe global patterns of biodiversity. HERE

This is a news article about a really important recent new paper that proved that some phenotypic traits (in this case plant flowering) can be completely controlled by heritable epigenetics.  This gives some evidence for the fact that epigenetics could have had a very important role in evolution. HERE

This research article on the gut microbiome and diet's links obesity in mice with transplanted microbiomes. HERE

Coming to you from this week's Nature

Linking gene expression profiles and regulatory variants
This study analyzed RNA-Seq data (mRNA and miRNA) generated from the lymphoblastoid cells lines of individuals whose genomes were sequenced as part of the 1000 Genomes Project. They were able to identify QTL (quantitative trait loci) associated both with gene expression levels and transcript ratios, or the ratio of distinct RNA transcripts for the same gene. The researchers found that QTLs were numerous and widespread, and, interestingly, that identified QTLs were enriched for indels. This research promises advances in understanding and characterizing regulatory variation in humans, as well as insights into phenotypic variation, when paired with GWAS data.


GMO endangered species!
This comment piece discusses "facilitated adaptation," or the process of introducing adaptive genetic variants into a population faced with the risk of extinction. Facilitated adaptation involves either hybridizing members of a threatened population with members of a better adapted population, which has already been performed with reported success, or, more controversially, using genetic engineering to directly introduce adaptive variants into the threatened population from either another population of the same species or an entirely different species. Such adaptive alleles might convey, for example, increased heat tolerance. However, the author cautions that transgenic alleles may cause complications by disrupting co-adaptive interactions in the endangered population. He further warns that the promotion of these sorts of approaches may encourage indifference toward climate change.

Monday, September 23, 2013,0,7435494.story

This obituary talks about a man named Stephen Crohn, who had a rare genetic mutation that made him immune to the AIDS virus. The connection to gene patenting and patenting in general came in when the Diamond Center received a patent to test people for this genetic mutation. Even though the Diamond Center received a patent for this test, Stephen Crohn did not receive any compensation for volunteering himself for these tests. Therefore, this news brings up the question as to whether or not companies that patent genes focused on rare mutations should be required to give compensation to the human subjects. Additionally, in reference to the papers we read for class today, it seems clear that this "genetic test" is not something naturally occurring in nature; therefore, it is reasonable that it was given a patent.
-Neil Pathak

Pa. considers labeling law for genetics that help achieve record yields of corn, soybeans

Farmers in Pennsylvania have been using genetically-modified corn and soybeans and are producing record yields.  However, consumers in the state are pushing for all GMOs to be labelled.  Maine and Connecticut already have laws in place requiring GMO labelling and Congress is also discussing similar legislation. Consumer groups worry that GMOs have not been tested for long term affects on humans.  Scientists at Penn State and plant breeders argue that people do not understand genetic modification, saying that it is just a faster version of processes found in nature.  The Food and Drug Administration, the USDA, and the Environmental Protection Agency all regulate which GMOs may be grown and sold in the US, and the FDA has determined that GMOs in general are safe for consumption. In recent polls though, 90% of Americans thought that GMOs should be labelled as such.

TALENs: A Widely Applicable Technology for Targeted Genome Editing

TALENs, or transcription activator-like effector nucleases, offer a new and efficient way to modify any gene sequences of interest that occur in living cells and organisms. TALENs are engineered nucleases that cleave DNA, alter the nucleotide sequence at the cleave site, and repair the cleave. The engineered nucleases are made up of proteins that can be customized to bind to a sequence-specific DNA-binding domain (a protein domain that recognizes DNA) that are fused to a nuclease that cleaves the DNA. This creates double-strand breaks on specific sites that are repaired by mechanisms that can be exploited to create sequence alterations. This is a new and much easier method for targeted genome editing, which has large implications for biological research as well as possibly holding strategies for combating genetic diseases.

Original Article:

Sunday, September 22, 2013

Review: Using Racial, Ethnic, and Ancestral Categories in Genetics Research

Scientific classification of people into groups has been a historically contentious issue, and the advent of Human Genetics research has made this issue of categorization even more pertinent. This article is a review that covers the myriad of human categorization issues that are inherent in conducting human genetics research. It highlights the potential for biological classifications of people to result in cultural controversy while touching on subjects such as biological classification of race and the social construct of race itself, and human genetic diversity and origins and using ancestry as a category. It also confronts issues such as sampling bias in racial categories, and the ease at which genetic components of disease can be misattributed. It concludes by offering useful alternatives to using these potentially harmful categories in human genetics research.

Economic Impact of Gene Patenting

The research of Dr. Heidi Williams (MIT) is revelant to class discussion (Topics in Anthropological Genetics) of both the sequencing of the human genome and the recent Supreme Court decision in the Myriad Genetics case. For her dissertation, Williams investigated whether patents on genes inhibit or promote research on those genes. She focused on genes patented by Celera during the sequencing of the human genome and her work was presented to the Supreme Court in the Myriad case. Williams found that there were fewer publications involving genes initially sequenced and patented by Celera, and that diagnostic tests for these genes were much less likely to have been developed by 2009.
This link is to a popular summary of her work:
This link is to an academic article she published based on her dissertation:

#potluck #humangenome #Myriad #intellectualproperty

Thursday, September 19, 2013

Human SNP Links Differential Outcomes in Inflammatory and Infectious Disease to a FOXO3-Regulated Pathway

Linked below is an interesting publication regarding an allele that is associated with greater susceptibility of suffering a disease.  The concepts of this paper are (slightly) relevant to my project this year.  Here, they are looking at existing GWAS data to gain insight into the role of genetics on complex diseases and conditions.  What they found was that having a certain version of an allele (generated by a single SNP in the gene FOXO3A) can cause a human to have a much greater susceptibility to the disease.  The minor allele (“G”) is associated inflammatory diseases such as Crohns disease and rheumatoid arthritis.  On a molecular level, minor allele carriage was shown to limit inflammatory responses by reducing certain cytokines.  Overall, variability in prognosis is quite common in complex diseases, and this paper helps us to understand further a the link between genotype and phenotype of a disease.

Monday, September 16, 2013

NIH Studies Explore Ppromise Sequencing Babies' Genomes’-genomes

The NIH recently founded a study that will examine over the next 5 years the benefits and drawbacks of sequencing the genomes of babies when they are born.  Currently, newborns are tested for several disorders, like phenylketonuria, in which early treatments and therapies can prevent long term damage.  Several different hospitals will take similar, but distinct approaches to studying the usefulness of testing.  One will look for markers that can be used to predict drug overdoses in infants, and another will look at trying to diagnose infants that end up in neo-natal intensive care.  Yet another will divide infants into two groups, performing traditional testing on one and genome sequencing on the other, and then follow the children for several years to see how the information affected the children's health care.  Most of the participating groups will not examine all possible diseases and traits in the genome, but will instead focus on a list of important disorders, especially those that are treatable or preventable.

The Human Genome Project, GWAS, & the "Missing Heritability" Question

For many within the scientific and medical communities, as well as within the media and wider public, the sequencing of the human genome seemed to hold the promise of rapidly revealing the genetic basis of most common human diseases, as well as offer direction in the development of effective treatments. However, over a decade later, this outcome is widely considered to have failed. Much of this perceived failure is related to disappointment over the seemingly underwhelming results of the many genome-wide association studies (GWAS) published in the last six years. Initially anticipated to be a powerful way to link key human genetic variants with phenotypes, GWAS have tended instead to identify many alleles with very small affect on phenotype, leading to what has been dubbed the "missing heritability" problem. Possible explanations for missing heritability include a larger role of the environment in common diseases, the importance of alleles with large effects that occur in < 5% of the population, or the contribution of huge numbers of alleles of effect sizes to small to be detected by GWAS. This paper discusses how disappointment in GWAS is forcing a change in our understanding of the architecture of human disease and genetic heritability in humans more broadly.

#anthropologicalgenetics #humangenomeproject #potluck

Sunday, September 15, 2013

Nanopore Technology for DNA sequencing

Recently, NIH awarded a $17 million grant to eight research teams across the county for the purpose of investigating a nanopore technology for DNA sequencing. DNA sequencing was the major means of obtaining the full human genome sequence, and thus this new technology may pave the way towards learning more about the human genome. If such technology succeeds, it will have many advantages over current methods, according to this article. For instance, this new technology will potentially cost much less and enables scientists to reassess the same molecule multiple times. Exciting news!

-Neil Pathak

Saturday, September 14, 2013

Significance of Methylation in Divergence among Great Apes

In the September 5th issue of PLoS Genetics, Hernando-Herraez et al. present findings from a comparative study of CpG methylation patterns in great apes. The researchers generated methylation profiles from peripheral blood samples from nine humans, five chimpanzees, six bonobos, six gorillas, and six orangutans using the Illumina HumanMethylation platform. Notably, the authors found that great ape phylogeny could be recovered based on degree of divergence in methylation patterns. They were further able to identify many genes with lineage-specific methylation patters for all species, as well as enrichment for genes of species-specific functional categories. For example, in the case of humans, 171 uniquely methylated genes were identified showing enrichment related to neurological function and facial development. In particular, genes involved in semi-circular canal development in the inner ear were enriched for methylation in humans. This is especially interesting given the implication of this feature in maintaining balance during bipedal locomotion. 

Hernando-Herraez et al. further focused in on human-chimp differences by undertaking a pairwise comparison of a expanded dataset for the two species. Interestingly, they found that genes showing divergence in protein coding sequences were likely to also be differentially methylated, suggesting that molecular evolution may often combine sequence change and epigenetic change. However, they were also able to identify 184 genes that were conserved at the protein level between humans and chimps, but showed significant differences in promotor methylation, lending support to the frequently-invoked hypothesis that a substantial degree of phenotypic evolution along the chimpanzee and human lines is underlain by regulatory changes rather than changes at the protein level (King and Wilson, 1975; Ohno, 1971).

Hernando-Herraez I, Gilad Y, Prado-Martinez J, Garg P, Fernandez-Callejo M, Heyn H, Hvilsom C, Navarro A, Esteller M, Sharp A J and Marques-Bonet, T (2013). Dynamics of DNA Methylation in Recent Human and Great Ape Evolution. PLoS Genetics 9(9):e1003763.
King M and Wilson A (1975). Evolution at two levels in humans and chimpanzees. Science 188(4184):107-16.
Ohno, S (1971). Simplicity of mammalian regulatory systems inferred by single gene determination of sex phenotypes. Nature 234:134-137.

Thursday, September 12, 2013

International, interdisciplinary, multi-level bioinformatics training and education

International, interdisciplinary, multi-level bioinformatics training and education

This month, the journal Briefings in Bioinformatics published a special issue dealing with teaching bioinformatics to non-bioinformaticians.  There are a host of articles dealing with training strategies, bioinformatic applications in the life sciences, teaching bioinformatics in high school, etc.

Wednesday, September 11, 2013

genetic differentiation caused by isolation

This paper, recently published in the Journal of Human Genetics, sheds new light on the genetic differences between North African and Southwestern European populations.  Some believe that this area is a genetic "melting pot" while others believe it is clearly genetically distinct, and this paper argues for the latter.  Alu elements, SNP and STR were analyzed in established populations in each geographic location.  Genetic patterns were identified using sPCA; this method eliminated local genetic differentiation.  The study found that genetic differentiation between the populations is caused by isolation and not a barrier to gene flow such as cultural differences.