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A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA) (1). Here we performed a genome-wide association study meta-analysis in a total of > 100, 000 subjects of European and Asian ancestries (29, 880 RA cases and 73, 758 controls), by evaluating ~10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation (5), cis-acting expression quantitative trait loci (6) and pathway analyses (7-9)--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery., We conducted a three-stage trans-ethnic meta-analysis (Extended Data Fig. 1). On the basis of the polygenic architecture of RA10 and shared genetic risk among different ancestry (3, 4), we proposed [...]

The smoothened (SMO) receptor, a key signal transducer in the hedgehog signalling pathway, is responsible for the maintenance of normal embryonic development and is implicated in carcinogenesis. It is classified as a class frizzled (class F) G-protein-coupled receptor (GPCR), although the canonical hedgehog signalling pathway involves the GLI transcription factors and the sequence similarity with class A GPCRs is less than 10%. Here we report the crystal structure of the transmembrane domain of the human SMO receptor bound to the small-molecule antagonist LY2940680 at 2.5 Å resolution. Although the SMO receptor shares the seven-transmembrane helical fold, most of the conserved motifs for class A GPCRs are absent, and the structure reveals an unusually complex arrangement of long extracellular loops stabilized by four disulphide bonds. The ligand binds at the extracellular end of the seven-transmembrane-helix bundle and forms extensive contacts with the loops., The SMO receptor is an essential component of the canonical hedgehog signalling pathway, which has a key role in the regulation of embryonic development in animals (1,2). In vertebrates, the [...]

Zebrafish have become a popular organism for the study of vertebrate gene function (1,2). The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene [...]

Human epidemiological studies and studies of animal models provide many examples by which early life experiences influence health in a long-term manner, a concept known as biological embedding. Such experiences can have profound impacts during periods of high plasticity in prenatal and early postnatal life. Epigenetic mechanisms influence gene function in the absence of changes in gene sequence. In contrast to the relative stability of gene sequences, epigenetic mechanisms appear, at least to some extent, responsive to environmental signals. To date, a few examples appear to clearly link early social experiences to epigenetic changes in pathways relevant for mental health in adulthood. Our recent work using high-throughput epigenomic techniques points to large-scale changes in gene pathways in addition to candidate genes involved in the response to psychosocial stress and neuroplasticity. Elucidation of which pathways are epigenetically labile under what conditions will enable a more complete understanding of how the epigenome can mediate environmental interactions with the genome that are relevant for mental health. In this mini-review, we provide examples of nascent research into the influence of early life experience on mental health outcomes, discuss evidence of epigenetic mechanisms that may underlie these effects, and describe challenges for research in this area. Key words: epigenetics, DNA methylation, early life adversity, psychiatric disorders, animal models. Des etudes epidemiologiques realisees chez l'humain et des etudes portant sur des modeles animaux fournissent plusieurs exemples dans lesquels des experiences vecues tot dans la vie influencent la sante a long terme, un concept connu sous l'appellation de<>. De telles experiences peuvent avoir de profonds impacts durant les periodes de haute plasticite lors de la vie prenatale et tot apres la naissance. Les mecanismes epigenetiques influencent la fonction des genes en absence de changements dans leur sequence. A la difference de la relative stabilite des sequences geniques, les mecanismes epigenetiques semblent, du moins dans une certaine mesure, repondre aux signaux environnementaux. Jusqu'a present, quelques exemples semblent lier clairement des experiences sociales vecues precocement a des changements epigenetiques dans des sentiers pertinents a la sante mentale a l'age adulte. Nos recents travaux realises a l'aide de techniques epigenomiques a haut debit indiquent la presence de changements a grande echelle dans des sentiers geniques en plus des genes candidats impliques dans la reponse au stress psychosocial et la neuroplasticite. De savoir quels sont les sentiers labiles au plan epigenetique et sous quelles conditions ils le sont nous permettra de mieux comprendre comment l'epigenome peut intervenir dans les interactions de l'environnement avec le genome, qui sont pertinentes a la sante mentale. Dans cette mini-revue, nous donnons des exemples de la recherche emergente portant sur les experiences vecues tot dans la vie et leurs consequences sur la sante mentale, nous discutons des donnees qui revelent que des mecanismes epigenetiques peuvent sous-tendre ces effets, et nous decrivons les defis que pose la recherche dans ce domaine. [Traduit par la Redaction] Mots-cles: epigenetique, methylation d'ADN, epreuves vecues dans l'enfance, maladies psychiatriques, modeles animaux., Biological embedding and mental health The concept of biological embedding has gained substantial traction as a framework for understanding the roots of complex multifactorial phenomena in health and disease (McGowan [...]

Upon environmental changes or extracellular signals, cells are subjected to marked changes in gene expression (1,2). Dealing with high levels of transcription during replication is critical to prevent collisions between [...]

Human chromosome ends are capped by shelterin, a protein complex that protects the natural ends from being recognized as sites of DNA damage and also regulates the telomere-replicating enzyme, telomerase [...]

In mammals, one of the most pronounced consequences of viral infection is the induction of type I interferons, cytokines with potent antiviral activity. Schlafen (Slfn) genes are a subset of [...]

Haploinsufficiency of the SCN1A gene encoding voltage-gated sodium channel [Na.sub.v]1.1 causes Dravet's syndrome, a childhood neuropsychiatric disorder including recurrent intractable seizures, cognitive deficit and autism-spectrum behaviours. The neural mechanisms responsible for cognitive deficit and autism-spectrum behaviours in Dravet's syndrome are poorly understood. Here we report that mice with Scn1a haploinsufficiency exhibit hyperactivity, stereotyped behaviours, social interaction deficits and impaired context-dependent spatial memory. Olfactory sensitivity is retained, but novel food odours and social odours are aversive to Scnla1 2 mice. GABAergic neurotransmission is specifically impaired by this mutation, and selective deletion of [Na.sub.V]1.1 channels in forebrain interneurons is sufficient to cause these behavioural and cognitive impairments. Remarkably, treatment with low-dose clonazepam, a positive allosteric modulator of GABAA receptors, completely rescued the abnormal social behaviours and deficits in fear memory in the mouse model of Dravet's syndrome, demonstrating that they are caused by impaired GABAergic neurotransmission and not by neuronal damage from recurrent seizures. These results demonstrate a critical role for [Na.sub.V]1.1 channels in neuropsychiatric functions and provide a potential therapeutic strategy for cognitive deficit and autism-spectrum behaviours in Dravet's syndrome., Dravet's syndrome (DS), also called severe myoclonic epilepsy of infancy, is an intractable developmental epilepsy syndrome with seizure onset in the first year of life (1). However, unlike other generalized [...]

The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research., The human genome sequence provides the underlying code for human biology. Despite intensive study, especially in identifying protein-coding genes, our understanding of the genome is far from complete, particularly with [...]

DNase I hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify ~2.9 million DHSs that encompass virtually all known experimentally validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns. We connect ~580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is organized with dozens to hundreds of co-activated elements, and the transcellular DNase I sensitivity pattern at a given region can predict cell-type-specific functional behaviours. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation., Cell-selective activation of regulatory DNA drives the gene expression patterns that shape cell identity. Regulatory DNA is characterized by the cooperative binding of sequence-specific transcriptional regulatory factors in place of [...]

The biological function and evolution of microRNAs (miRNAs), an important class of noncoding regulatory genes, have attracted wide interest. However, their evolutionary impact on gene order rearrangements remains unknown. We examined the gene-order stability of miRNA-neighboring regions by a comparative human-mouse genomic analysis and found that the neighboring genes of human miRNAs tend to have a conserved gene order. This observation cannot be attributed to the functional bias of neighboring genes, and is a unique characteristic of miRNAs but not other noncoding RNAs. Our findings suggest that mammalian miRNAs stabilize the genomic architecture in evolution. Key words: microRNA, gene order, linkage conservation, mammalian genome. La fonction biologique et l'evolution des microARN (miRNA), une classe importante de genes non-codants impliques dans la regulation, font l'objet d'un grand interet. Cependant, leur impact evolutif sur les rearrangements de l'ordre genique demeure inconnu. Les auteurs ont examine la stabilite de l'ordre genique dans les regions bordant les miRNA lors de comparaisons genomiques entre les genomes humain et murin et ils ont observe que l'ordre des genes bordant les miRNA etait conserve chez l'humain. Cette observation ne peut pas etre attribuee a un biais fonctionnel de ces genes et constitue une caracteristique unique des miRNA car elle n' est pas partagee avec les autres ARN non-codants. Ces resultats suggerent que, chez les mammiferes, les miRNA stabilisent l'architecture genomique au cours de l'evolution. Mots-cles : microARN, ordre genique, conservation de la liaison genetique, genome de mammifere. [Traduit par la Redaction], Introduction MicroRNAs (miRNAs) are a major class of post-transcriptional regulatory genes (Ambros 2004; Bartel 2004; Zamore and Haley 2005). These short noncoding RNAs mainly bind to the 3'-untranslated regions of [...]

The present study is the first meta-analysis to evaluate type 2 diabetes (T2D)- associated polymorphisms in cohorts originated from several Tunisian regions. In fact, we evaluated the effect of seven polymorphisms in the following genes--PPARg (Pro12Ala), TNFα (-308A/G), ENPP1(K121Q), TCF7L2(rs7903146°C/T), MTHFR(C677T), ACE(I/D), and CAPN10(3R/2R)--on T2D risk, through a meta-analysis combining data of previous studies performed on Tunisian populations originating from the north, center, or south of the country. R statistics version 2.12.1 software was used to estimate the heterogeneity between studies. Pooled odds ratios were computed by the fixed-effects method of Mantel-Haenszel if no heterogeneity between studies exists. Despite the similarities founded in a number of loci, the Woolf test reported that the contributions of ENPP1 and ACE loci in T2D risk are dependent on the geographic origin of concerned groups, and this heterogeneity could be attributed not only to the variable contribution of the variant in T2D risk but also to diversities of genetic background between tested groups. Interestingly, observed heterogeneity highlighted founding concerning Y chromosome and the mitochondrial DNA about the genetic structure of Tunisian population and proves once again that Tunisians, like the north-Africans, are a mosaic of subpopulations, with significant differences in genetic structure. In homogeneous groups, we replicated the association of single-nucleotide polymorphisms of TCF7L2, MTHFR, CAPN 10, TNFα, and ACE genes with a T2D risk in the Tunisian population with OR ranging from 1.43 to 6.72. However, we reported an absence of the association of PPARg with T2D in the Tunisian population. KEY WORDS: TYPE 2 DIABETES, POLYMORPHISM GENES, GENETIC HETEROGENEITY., The worldwide prevalence of type 2 diabetes (T2D) is projected to nearly double by the year 2025 (Kiberstis 2005). In the Tunisian population, the prevalence of T2D reaches 9% of [...]

This study investigated: (1) the mitochondrial DNA (mtDNA) genetic variation in 116 unrelated individuals who originated from the Arabian Peninsula, Iran, or were of Bedouin ethnicity and (2) the genetic structure of Kuwaiti populations and compared it to their neighboring populations. These subpopulations were tested for genetic homogeneity and shown to be heterogeneous. Restriction fragment length polymorphism (RFLP) and mtDNA sequencing analyses of HVRI were used to reconstruct the genetic structure of Kuwait. The results indicated that the combined Kuwaiti population has a high frequency of haplogroup R0 (17%), J (12%), and U (12%) similar to other Arabian populations. In addition, contemporary African gene flow was detected through the presence of sub-haplogroup L (L1 and L2) (2%) and the absence of L3 which is reflective of an earlier migration. Furthermore, the multidimensional scaling (MDS) plot showed that the Kuwaiti population clusters with neighboring populations, including Iran and Saudi Arabia indicating gene flow into Kuwait. According to this study, the Kuwaiti population may be undergoing an expansion in a relatively short period of time, and the maternal genetic structure of Kuwait resembles both Saudi Arabia and Iran., Kuwait is located in the Arabian Peninsula on the coast of the Arabian Gulf (Figure 1). Kuwait is bordered by Iraq on the north and Saudi Arabia on the south. [...]

The Hamshenis are an isolated geographic group of Armenians with a strong ethnic identity who, until the early decades of the twentieth century, inhabited the Pontus area on the southern coast of the Black Sea. Scholars hold alternative views on their origin, proposing Eastern Armenia, Western Armenia, and Central Asia, respectively, as their most likely homeland. To ascertain whether genetic data from the nonrecombining portion of the Y chromosome are supportive of any of these suggestions, we screened 82 Armenian males of Hamsheni descent for 12 biallelic and 6 microsatellite Y-chromosomal markers. These data were compared with the corresponding data set from the representative populations of the three candidate regions. Genetic difference between the Hamshenis and other groups is significant and backs up the hypothesis of the Armenian origin of the Hamshenis, indicating central historical Armenia as a homeland of the ancestral population. This inference is further strengthened by the results of admixture analysis, which does not support the Central-Asian hypothesis of the Hamshenis' origin. Genetic diversity values and patterns of genetic distances suggest a high degree of genetic isolation of the Hamshenis consistent with their retention of a distinct and ancient dialect of the Armenian language. KEY WORDS: Y CHROMOSOME, MICROSATELLITE HAPLOTYPES, HAMSHENIS, GENETIC ANTHROPOLOGY., The Hamshenis represent an Armenian-speaking group, which is distinguished by the use of a particular dialect (Homshetsma) of the Western-Armenian language. Currently, they mainly inhabit the Black Sea coastal areas [...]

Identifying ancestry along each chromosome in admixed individuals provides a wealth of information for understanding the population genetic history of admixture events and is valuable for admixture mapping and identifying recent targets of selection. We present PCAdmix (available at https://sites.google.com/site/pcadmix/home), a Principal Components-based algorithm for determining ancestry along each chromosome from a high-density, genome-wide set of phased single-nucleotide polymorphism (SNP) genotypes of admixed individuals. We compare our method to HAPMIX on simulated data from two ancestral populations, and we find high concordance between the methods. Our method also has better accuracy than LAMP when applied to three-population admixture, a situation as yet unaddressed by HAPMIX. Finally, we apply our method to a data set of four Latino populations with European, African, and Native American ancestry. We find evidence of assortative mating in each of the four populations, and we identify regions of shared ancestry that may be recent targets of selection and could serve as candidate regions for admixture-based association mapping. KEY WORDS: ADMIXTURE, PRINCIPAL COMPONENTS ANALYSIS (PCA), LOCAL ANCESTRY DECONVOLUTION, HAPLOTYPE-BASED, FORWARD-BACKWARD ALGORITHM., There is increasing awareness that admixed individuals such as African Americans or Latinos may have a broad range of ancestry proportions, with varying ancestry proportions throughout the genome even within [...]

Nomadic populations have played a significant role in the history of not only China but also in many nations worldwide. Because they had no written language, an important aspect in the study of these people is the discovery of their tombs. It has been generally accepted that Xiongnu was the first empire created by a nomadic tribe in the 3rd century BC. However, little population genetic information is available concerning the Donghu, another flourishing nomadic tribe at the same period because of the restriction of materials until the Jinggouzi site was excavated. In order to test the genetic characteristics of ancient people in this site and to explore the relationship between Jinggouzis and Donghus, two uniparentally inherited markers were analyzed from 42 human remains in this site, which was located in northern China, dated approximately 2500 years ago. With ancient DNA technology, four mtDNA haplogroups (D, G, C, and M10) and one Y chromosome haplogroup (C) were identified using mitochondrial DNA and Y-chromosome single nucleotide polymorphisms. Those haplogroups are common in North Asia and East Asia. The Jinggouzi people were genetically closest to the Xianbeis in ancient populations and to the Oroqens among extant populations, who were all pastoralists. This might indicate that ancient Jinggouzi people were nomads. Meanwhile, according to the genetic data and the evidences in archaeology, we inferred that Jinggouzi people were associated with Donghu. It is of much value to trace the history of the Donghu tribe and this might show some insight into the ancient nomadic society. KEY WORDS: ANCIENT DNA, MITOCHONDRIAL DNA, Y-CHROMOSOME SINGLE NUCLEOTIDE POLYMORPHISMS, NOMADS, DONGHU, JINGGOUZI., Many significant nomadic groups have roamed the eastern regions of the Eurasian steppes in both prehistorical and historical times. As ancient nomads migrated frequently due to the natural environment and [...]

The human X and Y chromosomes evolved from an ordinary pair of autosomes during the past 200-300 million years (1-3). The human MSY (male-specific region of Y chromosome) retains only three percent of the ancestral autosomes' genes owing to genetic decay (4,5). This evolutionary decay was driven by a series of five 'stratification' events. Each event suppressed X-Y crossing over within a chromosome segment or 'stratum', incorporated that segment into the MSY and subjected its genes to the erosive forces that attend the absence of crossing over (2,6). The last of these events occurred 30 million years ago, 5 million years before the human and Old World monkey lineages diverged. Although speculation abounds regarding ongoing decay and looming extinction of the human Y chromosome (7-10), remarkably little is known about how many MSY genes were lost in the human lineage in the 25 million years that have followed its separation from the Old World monkey lineage. To investigate this question, we sequenced the MSY of the rhesus macaque, an Old World monkey, and compared it to the human MSY. We discovered that during the last 25 million years MSY gene loss in the human lineage was limited to the youngest stratum (stratum 5), which comprises three percent of the human MSY. In the older strata, which collectively comprise the bulk of the human MSY, gene loss evidently ceased more than 25 million years ago. Likewise, the rhesus MSY has not lost any older genes (from strata 1-4) during the past 25 million years, despite its major structural differences to the human MSY. The rhesus MSY is simpler, with few amplified gene families or palindromes that might enable intrachromosomal recombination and repair. We present an empirical reconstruction of human MSY evolution in which each stratum transitioned from rapid, exponential loss of ancestral genes to strict conservation through purifying selection., The human Y chromosome no longer engages in crossing over with its once-identical partner, the X chromosome, except in its pseudoautosomal regions. During evolution, X-Y crossing over was suppressed in [...]

The number of centenarians is growing worldwide. This specific cohort has aroused the attention of scientists worldwide and is considered one of the most valuable models to study the mechanisms involved in the aging process. In fact, they have reached the extreme limits of human life span and, most important of all, they show relatively good health being able to perform their routine daily life. Because they have escaped the common lethal diseases, the role of their genetic background has been brought into focus. In fact, sequence variations, in a variety of pro- or anti-inflammatory cytokine genes, have been found to influence successful ageing and longevity. The key role played by cytokines has been also confirmed in centenarians as we know that inflammation has been related to several pathological burdens (e.g., obesity, atherosclerosis, and diabetes). Successful ageing seems to be related to an optimal functioning of the immune system, pointing out that polymorphisms for the immune system genes, which are involved in the regulation of immune-inflammatory responses, may play a key role in the genetics of ageing. This review provides an update in the field of ageing related to inflammation and genetics. KEY WORDS: CENTENARIANS, ELDERLY, INFLAMMATION, CYTOKINES, ADIPOKINES, GENETICS, AGING., Statistics. The number of centenarians is growing worldwide. According to the report 'World Population Ageing 2009,' by the United Nations Department of Economic and Social Affairs/Population Division, there were an [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.forsciint.2010.02.029 Byline: Ronny Decorte (a)(b) Keywords: DNA profiling; Genetic identification; Physical traits; Geographic origin Abstract: In 2010, it is the 25th anniversary of the first paper describing the genetic identification of human individuals by DNA fingerprint analysis. Since then DNA analysis has become a major tool to relate biological evidence to the persons involved in a crime or to determine the biological relationship among individuals. The currently used methodology is the result of major technological changes that were partly driven by criticism on previous methodologies, and partly driven by demand especially due to mass disasters such as the '9/11 attack' on the World Trade Center in New York. This review will give an overview of the current methodology in genetic identification and new developments that will have a future impact on forensic identification. Author Affiliation: (a) University Hospitals Leuven, Department of Forensic Medicine, Leuven, Belgium (b) University of Leuven, Department of Human Genetics, Leuven, Belgium Article History: Received 2 February 2010; Accepted 23 February 2010

Copy number variation in the human genome is prevalent but relatively little is known about the dynamics of DNA rearrangement. We therefore used the duplicated [gamma]-globin genes as a simple system to explore de novo copy number changes. Rearrangements that changed gene number were seen in both germline and somatic DNA, and mainly arose by unequal sister chromatid exchange between homologous sequences, with evidence from recurrent mosaic rearrangements that many, if not all, of these events in sperm arise before meiosis. Unequal exchange frequencies are apparently controlled primarily by the degree of sequence identity shared by the duplicate genes, leading to substantial variation between haplotypes in copy number instability. Additional, more complex rearrangements generated by mechanisms not involving homologous recombination, and in some cases showing DNA transfer between chromosomes, were also detected but were rare. Sequence changes were also seen in [gamma]-globin DNA molecules, with strong evidence that some were genuine de novo base substitutions. They were present in sperm at a frequency far higher than predicted from current estimates of germline mutation rates, raising interesting questions about base mutation dynamics in the male germline. base mutation | blood | ectopic | recombination | sperm doi/ 10.1073/pnas.1003634107

The cytosolic domain of Notch is a membrane-tethered transcription factor. Ligand binding ultimately leads to [gamma]-secretase cleavage within the transmembrane domain, allowing the intracellular domain to translocate to the nucleus and activate target gene transcription. Constitutive Notch signaling has been associated with human cancers such as T cell acute lymphoblastic leukemia (T-ALL). As tetraspanins have been implicated in many different signaling processes, we assessed their potential contribution to Notch signaling. We used a genetic assay in Caenorhabditis elegans to identify TSP-12 as a positive factor for Notch activity in several cellular contexts. Then, using a cell culture system, we showed that two human TSP-12 orthologs, TSPAN33 and TSPAN5, promote Notch activity and are likely to act at the [gamma]-secretase cleavage step. We also acquired evidence for functional redundancy among tetraspanins in both C, elegans and human cells. Selective inhibition of tetraspanins may constitute an anti-NOTCH therapeutic approach to reduce [gamma]-secretase activity. cancer | development | [gamma]-secretase doi/10.1073/pnas.1001647107

A study undertakes systems genetics analysis of gene by environment (GxE) interactions in human cells in order to analyze human primary endothelial cell responses to proinflammatory oxidized phospholipids involved in cardiovascular disease. Results highlight a significant presence of GxE interactions, suggesting that GxE interactions which affect gene expression may be a key characteristic of complex disease.

Studies offer insights into the geographical and racial distribution of the polymorphic inversion on 17q21, also called the microtubular associated protein tau (MAPT) inversion) in humans. Data analysis also suggests that the most recent common ancestor for the H2 haplotype inversion could be dated at about 13,600 to 108, 400 years earlier, much more recent than the 3 million year date previously suggested.