Interface Newsletter: Issue 32 — summer and fall 2006


Cough Syrup Disaster…………………1
Evolutionarily Speaking……………….4
Latest in Genetics and Genomics…….7
Human Variation………………………..7
Observations by a Biologist…………….9
Ethical, Legal and Social Issues……10
Letters to the Editor……………………….12
Gene-Environment Tidbits………….5
Welcome, New Director ……………..11

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Interface Newsletter: Issue 9 — fall 1996

Environmental Pollution and Child Health in Central and Eastern Europe……………………………………………….1
Letters to the Editor…………………………….3
Happy Birthday to You………………………..5
CEG Members in the News…………………..6
Jigsaw Puzzle Gene……………………………..6
CEG-Sponsored Speakers…………………….6
Science Lite………………………………………..7
Observations by a Biologist………………….8
Who Should Regulate Genetic Testing?…8

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Novel Cobamide Structure Perhaps More Effective at Biological Degradation of Chlorinated Compounds???

This is the summary of a recent successful Superfund Project, funded by the National Institute of Environmental Health Sciences (NIEHS).

Novel Cobamide Structure Perhaps More Effective at Biological Degradation of Chlorinated Compounds?

Researchers at the University of Tennessee have discovered a compound that helps specific bacteria degrade pollutants like polychloroethene (PCE). This compound, called purinyl-cobamide, assists enzymes during degradation reactions.

Researchers identified purinyl-cobamide in a study led by Superfund Research Program grantee Frank Loeffler, PhD. These helper molecules are part of a larger group of chemical structures known as cobamides. A majority of organisms, including humans, require cobamides for normal functioning. Vitamin B12 is the best-known member of this group of helper molecules.

Investigating how Chemical Structure Affects Molecular Function

The researchers previously discovered that changes to the lower base structure of cobamides influence the bioremediation efficiency of the bacterium Dehalococcoides mccartyi, a key organism for in situ treatment of toxic chlorinated compounds. They found that minor structural differences in the lower base affected whether degradation of PCE stopped at vinyl chloride, a carcinogen, or proceeded all the way to non-toxic ethene. Since Dehalococcoides cannot synthesize its own helper molecules, the findings emphasize the importance of understanding how other microorganisms interact with Dehalococcoides and enable efficient detoxication.

Desulfitobacterium uses unsubstituted purine to form purinyl-cobamide, a helper molecule that initiates PCE detoxification.Building on this work, they investigated the structure of the helper molecules involved when a different type of bacterium, Desulfitobacterium hafniense, partially degrades PCE. Combining cultivation and sophisticated analytical techniques, they found that Desulfitobacterium uses unsubstituted purine to build a functional cobamide that enables PCE degradation. Interestingly, the Desulfitobacterium cobamide does not support Dehalococcoides dechlorination activity, and knowledge and availability of the correct lower base type is crucial to sustain the activity of bacteria involved in priority pollutant detoxication.

Many types of substituted purine bases, which are derivatives of unsubstituted purine, have known biological functions, including those as essential building blocks of DNA. However, unsubstituted purine, which gives its name to the wider class of molecules, was not assigned a specific biological function until now.

Implications for Environmental Cleanup and Human Health

This study further demonstrates that the type of lower base in the cobamide structure plays an important role in the function of enzymes to speed up degradation of chlorinated compounds by bacteria. Understanding the biological and geochemical conditions that support the production of specific cobamides, which efficiently promote dechlorination to non-toxic end products, may lead to faster detoxication at contaminated waste sites, and can substantially reduce cleanup costs.

These findings also expand the diversity of naturally occurring cobamide structures and assign the first biological function to unsubstituted purine. Enzymes that depend on cobamides fulfill essential metabolic functions in most organisms, including mammals. As a result, a better understanding of how the lower base of the cobamide structure controls enzyme activity may be relevant to any natural and engineered microbiome, and even have implications for the progression of certain human diseases.

For more information, contact:

Frank E. Loeffler, PhD
University of Tennessee
Department of Microbiology

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Multi-ethnic genome-wide association study (GWAS) reveals polygenic architecture of earlobe attachment

I can still remember the day when one of my sons (and he was certainly no more than 6 years old) was deep in thought and then asked, “How many genes do you think it would take to make a jaw?” After picking myself up off the floor, I began explaining to him that “to form any facial features” must take a large number of contributing genes (but I didn’t go into defining “multifactorial trait” for him at that time). Earlobe attachment is another “facial features” trait (phenotype) that helps to define the appearance of each individual, and clearly (if one has sat on a bus in New York City or London, and noticed different ethnic groups) the trait seems to be linked to other aspects of ethnic facial features.

As early as 1937, a geneticist [J Hered 1937; 28: 425-236] had pointed out that earlobe attachment is likely to be “a polygenic trait” (i.e. phenotype reflected by the contribution of multiple, or many, genes) “exhibiting a continuous phenotypic distribution.” Although earlobe attachment is a neutral morphological trait (i.e. no apparent survival or reproductive advantage) –– understanding its genetic etiology is valuable in that it offers a glimpse into the biological basis of ear development, improving our understanding of genes potentially involved in developmental (birth) defects. Moreover, it serves as an instructive example of simple versus polygenic inheritance in an accessible, easy-to-observe-and-measure trait.

Recent genome-wide association studies (GWASs) have investigated earlobe attachment and reported significant associations with variants in the EDAR and SP5 genes. However, these (and other suggested associations with specific genetic loci) have yet to be replicated in independent additional studies. Of note, ethnic differences in the frequency of earlobe attachment are well documented, suggesting that genetic heterogeneity might underlie the trait and that deciphering its genetic architecture might require studies across numerous ethnic groups. This notion is supported by the fact that one of the two previously reported associations was with a missense EDAR variant (i.e. DNA base change that alters an amino acid) that is common in Asian and Amerindian populations but absent or infrequent in European and African populations.

Authors [see attached article] performed a GWAS of earlobe attachment in a multi-ethnic sample of 74,660 individuals from four cohorts (three with the trait scored by an expert rater, and one with the trait self-reported). Meta-analysis of the three expert-rater-scored cohorts revealed six associated loci harboring numerous candidate genes –– including EDAR, SP5, MRPS22, ADGRG6, KIAA1217, and PAX9. These genes and their functions can be searched for on the web site.) The large self-reported 23andMe cohort recapitulated each of these six loci. Moreover, meta-analysis across all four cohorts revealed a total of 49 significant (P <5.0 x 10–8) loci. Intriguingly, annotation and enrichment analyses of these 49 loci showed strong evidence of genes involved in ear development and syndromes with auricular phenotypes. RNA-sequencing data from both human fetal ear and mouse second branchial arch tissue confirmed that genes located among associated loci showed evidence of expression. These exciting results provide strong evidence for the polygenic nature of earlobe attachment and offer insights into the biological basis of normal and abnormal ear development. Am J Hum Genet 7 Dec 2o17; 101: 913–924

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High-throughput annotation of full-length long noncoding RNAs (lncRNAs) — success using RNA Capture Long Seq (CLS)

Long noncoding RNAs (lncRNAs), formerly called “long intergenic noncoding RNAs” (lincRNAs), represent a vast and relatively unexplored component of the mammalian genome. They are defined as “>200 nucleotides, and up to many thousands of nucleotides, that are transcribed into RNA but not translated in a protein product.” LncRNAs have been implicated in associations with certain human complex diseases (e.g. schizophrenia, autism spectrum disorder, and cancers) and therefore are relevant to “gene-environment interactions” because LncRNAs are yet-another form of GENOTYPE that influences/affects the PHENOTYPE (multifactorial trait).

Assignment of lncRNA functions depends on the availability of high-quality transcriptome (mRNAs, coding RNA, transcribed from DNA) annotations. At present, such annotations are still rudimentary: we have little idea of the total number of lncRNAs, and for those that have been identified, transcript structures remain largely incomplete. Projects –– using diverse approaches –– have helped to increase both the number and size of available lncRNA annotations. Early gene sets, derived from a mixture of FANTOM cDNA sequencing efforts and public databases, were combined with lncRNA sets discovered through chromatin signatures. More recently, researchers have applied transcript-reconstruction software, but annotation efforts continue to face a necessary compromise between throughput and quality. Hence, there is growing divergence between large automated annotations of uncertain quality (e.g. 101,700 genes for NONCODE versus 15,767 genes for GENCODE version 25).

Annotation incompleteness takes two forms. First, genes may be entirely missing from an annotation; many genomic regions are suspected to transcribe RNA but contain no annotation, including ‘orphan’ small RNAs with presumed long precursors, enhancers, and ultra-conserved elephants. Second, annotated lncRNAs may represent partial gene structures. Start- and end-sites frequently lack independent supporting evidence, and lncRNAs are shorter and have fewer exons than mRNAs. To accelerate lncRNA annotation, the GENCODE consortium has developed RNA Capture Long Seq (CLS), which combines targeted RNA-capture with third-generation long-read sequencing. Authors [attached article] present an experimental reannotation of the GENCODE intergenic lncRNA populations in matched human and mouse tissues –– that resulted in novel transcript models for 3,574 and 561 gene loci, respectively.

CLS approximately doubled the annotated complexity of the targeted loci, outperforming existing short-read techniques. Full-length transcript models produced by CLS enabled these authors definitively to characterize the genomic features of lncRNAs –– including promoter and gene structure, and protein-coding potential. Therefore, CLS can remove a long-standing bottleneck in transcriptome annotation, by generating manual-quality full-length transcript models at high-throughput scales.

Nat Genet Dec 2o17; 49: 1731–1740

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Decreased mutation rate in exons — discovered to be due to differential DNA mismatch repair

A mutation usually means “the change in one base” [one nucleotide in the haploid genome; one base-pair (bp) in the diploid genome], but sometimes “mutations” can include any changes –– from a single bp alteration to many bases (two, five, 50, hundreds or thousands) inserted, deleted, and/or inverted). And it has long been known that mutations more readily occur in noncoding regions (introns, intra-genic areas of DNA) than in coding regions (DNA giving rise to the mRNA which in turn gives rise to the protein). The “mutational landscape of the genome” is very com­plex. Decades ago, traditional models of evolutionary and population genetics had (naïvely) proposed that mutations occur ran­domly with respect to time, genomic position, and mutation type. Under such models, muta­tions were expected to occur uniformly through­out the genome, and deviations from this expectation could potentially indicate selective pressures (DNA changes due to environmental pressures, conferring a resultant advantage, i.e. reproduction and survival).

Then CpG dinucleotides (CG on one strand; CG also on the other strand) were found to be mutational hotspots –– having enhanced muta­tion rates, subsequently shown to be driven by frequent deamination of methylated cytosines –– marked the beginning of the realization that the null model of mutation could not be true. More recently, next-generation sequencing (NGS) of tumors, families, and popula­tions has identified a mutational landscape with biases –– ranging from the level of single-nucleotides to that of the whole genome. At the sequence level, it has now become clear that the probability of a given nucleotide mutating is primarily determined by its flanking upstream and downstream neighbors. Likewise, transcription factors and other DNA-binding proteins exclude repair factors from sequences that span 10-20-30 base pairs.

Chromatin states also influence muta­bility of sequences of hundreds to thousands of bp in length, DNA replication tim­ing exerts significant pressures on the mutational properties of megabase-scale regions, and the sex and age of parents can influence genome-level patterns of de novo mutation in their gametes (sperm, ova). Interestingly, all of these lev­els of bias appear to interact with one another to generate a highly complex landscape of genomic mutation. A detailed understanding of this landscape is instrumental to studies of genetic inheritance, evolution, and tumorigen­esis. The [attached] report provides insight into yet another layer of mutational complexity –– one that has been hiding right under our noses, yet has gone undetected owing to the difficulty of teasing apart mutational processes from signs of “natural selection”. This new study shows that, independently of purifying selection, mutation rates in gene exons are lower than predicted when analyzing their sequence composition. Rather, authors show that ‘fewer somatic mutations in exons than expected from their sequence content’ are caused by higher mismatch-repair activity in exonic than in intronic regions. These data have important implications in understanding the evolution of eukaryotic genes, and they have practical ramifications for the study of evolution of both tumors and species.

Nat Genet Dec 2o17; 49: 1684–1692 [article] & pp 1673–1674 [editorial]

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Maternal age elicits phenotypic variation in the Caenorhabditis elegans (nematode)

For years, on these pages of “Gene-Environment Interactions,” we’ve pointed out that the genotype [dependent on: DNA alterations (i.e. genetics), epigenetic changes (i.e. DNA-methylation, RNA-interference, histone modifications, chromatin remodeling), adverse environmental effects, and even obscure (poorly understood) transgenerational effects] reflects the ultimate phenotype (trait) that is seen. This can be a Mendelian trait involving just a few “large-effect” genes, or a multifactorial trait involving hundreds or thousands of genes, most of which have small-effect. Interestingly, the topic of this publication [attached] involves “maternal age” as an (unexpected?) factor that contributes to phenotypic variation. (Albeit the animal model system being studied here is the (lowly) tiny roundworm, Caenorhabditis elegans, which is about 1-mm in length.)

Genetically identical individuals that grow in the same environment often show substantial phenotypic variation within populations of organisms –– as diverse as bacteria, invertebrates such as flies and worms, and vertebrates such as fish, frogs, rodents and humans. With some exceptions, the causes are poorly understood. Authors [see attached report] show that isogenic (“presumed to be genetically identical”) Caenorhabditis elegans nematodes vary in their size at hatching, speed of development, rate of growth, starvation resistance, fecundity (rate of fertility), and also in the rate of development of their germline (development of sperm and ova) relative to that of somatic tissues. These six underlined characteristics in this paragraph can all be defined as traits (phenotypes).

Authors demonstrated that the primary cause of this variation is the age of each individual nematode’s mother –– with the progeny of young mothers exhibiting several phenotypic impairments. They identified age-dependent changes in maternal provisioning of the lipoprotein complex vitellogenin to embryos as the pivotal molecular mechanism that underlies the variation in multiple traits throughout the life of an animal. Authors suggest (but I’m not so sure about it) that production of sub-optimal progeny by young mothers might reflect a trade-off between the competing fitness traits of “a short generation-time” and the “survival and fecundity” of the progeny.

Nature 7 Dec 2o17; 552: 106–109

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Genetic diversity of the African malaria vector, the Anopheles gambiae mosquito: evidence for recent selection in insecticide-resistant genes

This topic is very central to “gene-environment (GxE) interactions.” Plasmodium falciparum is the disease-causing protozoan parasite that causes the infectious disease MALARIA in humans and other primates (which are called “the host”), and the blood-sucking mosquito Anopheles gambiae species is the vector that transmits the blood-borne disease from one host to another future host. Treating the mosquito with various insecticides can prevent malaria in humans by killing the vector. Yet, the mosquito’s DNA is able to mutate (DNA alterations) and the mosquito’s epigenome is probably also able to “re-adjust” to such adversity (i.e. some drug that wants to kill the mosquito) in order to survive. And survival of the mosquito is what we humans and clinical medicine do not want to happen.

Substantial decreases in the incidence of malaria morbidity and mortality have been achieved by the use of insecticide-based interventions, but increasing levels of insecticide resistance, and other adaptive changes in mosquito populations, threaten to reverse these achievements. A better understanding of the molecular, ecological and evolutionary processes driving these changes is essential to maximize the active “beneficial duration” of existing insecticides, and to accelerate development of new strategies and tools for vector control. The Anopheles gambiae 1000 Genomes Project (Ag1000G; was established to provide a foundation for detailed investigation of mosquito genome variation and evolution.

Authors [see attached article] describe here the first phase of the project, which analyzed 765 wild-caught specimens of Anopheles gambiae sensu stricto and Anopheles coluzzii. These two species account for the majority of malaria transmission in Africa, and are morphologically indistinguishable and often sympatric (i.e. occurring within the same geographical area; overlapping in distribution), but are genetically distinct and differ in geographical range, larval ecology, behavior, and strategies for surviving the dry season. The specimens were collected at 15 locations across eight African countries, spanning a range of ecologies including rainforest, inland savannah and coastal biomes, and thus provide a broad sample in which to explore factors shaping mosquito population variation. To gain a deeper understanding of how mosquito populations are evolving, authors identified >50 million single nucleotide variants. They found complex population structure and patterns of gene flow –– with evidence of ancient expansions, recent bottlenecks, and local variation in effective population size. Strong signals of recent selection were observed in insecticide-resistance genes, with several sweeps spreading over large geographical distances and between species. The design of new tools for mosquito control, using gene-drive systems, will need to take into account the high levels of genetic diversity in natural mosquito populations.
Nature 7 Dec 2o17; 552: 96–100

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Asian perspectives on the origin of modern human populations

In spite of the general acceptance that modern humans (Homo sapiens) arose in Africa, information about the initial arrival and survival of modern humans in different areas of the world continues to be discovered and updated. Over the past several decades, Asia has been receiving increasing attention, particularly because it is considered the conduit through which Homo sapiens arrived in distant regions such as Western Europe, Australia, and eventually the Americas. Even more importantly, the Asian continent –– bounded by the Pacific, Indian, and Arctic Oceans and Europe to the west, includes a wide range of latitudinal, longitudinal, and even altitudinal variation –– which has major implications for human evolution.

The questions of what, where, how, and especially why with regard to our becoming “human” continue to be of great interest. This is why we continue to study closely and evaluate all the evidence on modern human origins and, specifically, how the Asian record contributes to addressing such questions. Findings from archaeology, hominin paleontology, geochronology, genetics, and paleoclimatology have all been contributing to a better understanding of the Late Pleistocene

(126,000 ± 5,000 years ago) human evolutionary record in Asia. In the attached article, authors discuss some of the big questions that paleoanthropologists are investigating across Asia: Can modern human dispersal “Out of Africa” be considered a single event occurring only after 60,000 years ago, or is the picture more complicated? By which route(s) did modern humans disperse across Asia? What was the nature of the interactions between modern humans and hominin groups already present in Asia? What role did geographic and/or paleoenvironmental variations play in modern human dispersals?

The traditional “out of Africa” model, which hypothesizes a dispersal of modern Homo sapiens across Eurasia as a single wave at ~60,000 years ago, and the subsequent replacement of all indigenous populations, is clearly too simplistic and in need of extensive revision. Important findings highlighted here include growing evidence for multiple dispersals, predating 60,000 years ago in regions such as southern and eastern Asia. Modern humans moving into Asia met Neanderthals, Denisovans, mid-Pleistocene Homo, and possibly even Homo floresiensis, combined with some degree of interbreeding (admixture) occurring.These early human dispersals, which left at least some genetic traces in the DNA of modern populations, indicate that later migrations were not “pristine” but rather that interbreeding kept occurring and re-occurring.

Science 8 Dec 2o17; 358: 1269 + the 7-page article

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Genotype-Tissue Expression Project (GTEx) can be enhanced by bridging the gaps between genotype, gene expression, and disease

This brief overview article [attached] should interest those of you who wish to combine genotype data (DNA mutations) and gene expression (transcriptomics) with human diseases or other traits such as drug efficacy or toxicity (multifactorial traits). Identifying the molecular and cellular basis of human complex disease –– should provide new oppor­tunities for disease prevention and treatment. Genome-wide association studies (GWAS) have already yielded thousands of genetic associations –– localizing regions of the genome that confer increased disease risk. However, within disease-associated regions, causal variants and the mechanism of action often remain poorly understood. To address this challenge, the (previously launched) Genotype-Tissue Expression (GTEx) Project has generated a systematic, multi-tissue refer­ence for identifying genetic variants associated with changes in gene expression (expression quantitative trait loci, eQTLs).

The GTEx resource supports research into potential mechanisms of action for disease-associated variants. Beyond gene expression, a rapidly increas­ing array of molecular and sequencing-based assays is identifying genetic variants associated with many intermediate molecular pheno­types. Identifying any particular genetic variant’s downstream cascade of effects, from molecule to the individual, requires assaying multiple layers of molecular complexity. Authors [attached] introduce the latest innovation, the Enhancing GTEx (eGTEx) Project –– that extends the GTEx Project by combining gene expression with additional intermediate molecular measurements on the same tissues. These modifications and updates should provide a resource for studying how genetic differences cascade through molecular phenotypes to impact human health.

Nat Genet Dec 2o17; 49: 1664–1669

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