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1.  Thalamic and cortical pathways supporting auditory processing 
Brain and language  2012;126(1):22-28.
The neural processing of auditory information engages pathways that begin initially at the cochlea and that eventually reach forebrain structures. At these higher levels, the computations necessary for extracting auditory source and identity information rely on the neuroanatomical connections between the thalamus and cortex. Here, the general organization of these connections in the medial geniculate body (thalamus) and the auditory cortex is reviewed. In addition, we consider two models organizing the thalamocortical pathways of the non-tonotopic and multimodal auditory nuclei. Overall, the transfer of information to the cortex via the thalamocortical pathways is complemented by the numerous intracortical and corticocortical pathways. Although interrelated, the convergent interactions among thalamocortical, corticocortical, and commissural pathways enable the computations necessary for the emergence of higher auditory perception.
PMCID: PMC3483386  PMID: 22728130
thalamus; cortex; medial geniculate body; auditory; thalamocortical; corticocortical; commissural
2.  Diverse mechanisms of somatic structural variations in human cancer genomes 
Cell  2013;153(4):919-929.
Identification of somatic rearrangements in cancer genomes has accelerated through analysis of high-throughput sequencing data. However, characterization of complex structural alterations and their underlying mechanisms remains inadequate. Here, applying an algorithm to predict structural variations from short reads, we report a comprehensive catalog of somatic structural variations and the mechanisms generating them, using high-coverage whole-genome sequencing data from 140 patients across ten tumor types. We characterize the relative contributions of different types of rearrangements and their mutational mechanisms, find that ~20% of the somatic deletions are complex deletions formed by replication errors, and describe the differences between the mutational mechanisms in somatic and germline alterations. Importantly, we provide detailed reconstructions of the events responsible for loss of CDKN2A/B and gain of EGFR in glioblastoma, revealing that these alterations can result from multiple mechanisms even in a single genome and that both DNA double-strand breaks and replication errors drive somatic rearrangements.
PMCID: PMC3704973  PMID: 23663786
3.  Methanol oxidation by temperate soils and environmental determinants of associated methylotrophs 
The ISME Journal  2012;7(5):1051-1064.
The role of soil methylotrophs in methanol exchange with the atmosphere has been widely overlooked. Methanol can be derived from plant polymers and be consumed by soil microbial communities. In the current study, methanol-utilizing methylotrophs of 14 aerated soils were examined to resolve their comparative diversities and capacities to utilize ambient concentrations of methanol. Abundances of cultivable methylotrophs ranged from 106–108 gsoilDW−1. Methanol dissimilation was measured based on conversion of supplemented 14C-methanol, and occurred at concentrations down to 0.002 μmol methanol gsoilDW−1. Tested soils exhibited specific affinities to methanol (a0s=0.01 d−1) that were similar to those of other environments suggesting that methylotrophs with similar affinities were present. Two deep-branching alphaproteobacterial genotypes of mch responded to the addition of ambient concentrations of methanol (⩽0.6 μmol methanol gsoilDW−1) in one of these soils. Methylotroph community structures were assessed by amplicon pyrosequencing of genes of mono carbon metabolism (mxaF, mch and fae). Alphaproteobacteria-affiliated genotypes were predominant in all investigated soils, and the occurrence of novel genotypes indicated a hitherto unveiled diversity of methylotrophs. Correlations between vegetation type, soil pH and methylotroph community structure suggested that plant–methylotroph interactions were determinative for soil methylotrophs.
PMCID: PMC3635236  PMID: 23254514
aerated soil; amplicon pyrosequencing; mxaF; mch; fae; Michaelis–Menten kinetics
4.  Copy number variation prevalence in known asthma genes and their impact on asthma susceptibility 
Genetic studies have identified numerous genes reproducibly associated with asthma, yet these studies have focused almost entirely on single nucleotide polymorphisms (SNPs), and virtually ignored another highly prevalent form of genetic variation: Copy Number Variants (CNVs).
To survey the prevalence of CNVs in genes previously associated with asthma, and to assess whether CNVs represent the functional asthma-susceptibility variants at these loci.
We genotyped 383 asthmatic trios participating in the Childhood Asthma Management Program (CAMP) using a competitive genomic hybridization (CGH) array designed to interrogate 20,092 CNVs. To ensure comprehensive assessment of all potential asthma candidate genes, we purposely used liberal asthma gene inclusion criteria, resulting in consideration of 270 candidate genes previously implicated in asthma. We performed statistical testing using FBAT-CNV.
Copy number variation in asthma candidate genes was prevalent, with 21% of tested genes residing near or within one of 69 CNVs. In 6 instances, the complete candidate gene sequence resides within the CNV boundaries. On average, asthmatic probands carried 6 asthma-candidate CNVs (range 1–29). However, the vast majority of identified CNVs were of rare frequency (< 5%), and were not statistically associated with asthma. Modest evidence for association with asthma was observed for 2 CNVs near NOS1 and SERPINA3. Linkage disequilibrium analysis suggests that CNV effects are unlikely to explain previously detected SNP associations with asthma.
Although a substantial proportion of asthma-susceptibility genes harbor polymorphic CNVs, the majority of these variants do not confer increased asthma risk. The lack of linkage disequilibrium (LD) between CNVs and asthma-associated SNPs suggests that these CNVs are unlikely to represent the functional variant responsible for most known asthma associations.
PMCID: PMC3609036  PMID: 23517041
5.  Laser-scanning photostimulation of optogenetically targeted forebrain circuits 
The sensory forebrain is composed of intricately connected cell types, of which functional properties have yet to be fully elucidated. Understanding the interactions of these forebrain circuits has been aided recently by the development of optogenetic methods for light-mediated modulation of neuronal activity. Here, we describe a protocol for examining the functional organization of forebrain circuits in vitro using laser-scanning photostimulation of channelrhodopsin, expressed optogenetically via viral-mediated transfection. This approach also exploits the utility of cre-lox recombination in transgenic mice to target expression in specific neuronal cell types. Following transfection, neurons are physiologically recorded in slice preparations using whole-cell patch clamp to measure their evoked responses to laser-scanning photostimulation of channelrhodopsin expressing fibers. This approach enables an assessment of functional topography and synaptic properties. Morphological correlates can be obtained by imaging the neuroanatomical expression of channelrhodopsin expressing fibers using confocal microscopy of the live slice or post-fixed tissue. These methods enable functional investigations of forebrain circuits that expand upon more conventional approaches.
PMCID: PMC3966657  PMID: 24430760
optogenetics; cortex; thalamus; channelrhodopsin; photostimulation; auditory; visual; somatosensory
6.  Expression and Characterization of Coprothermobacter proteolyticus Alkaline Serine Protease 
The Scientific World Journal  2013;2013:396156.
A putative protease gene (aprE) from the thermophilic bacterium Coprothermobacter proteolyticus was cloned and expressed in Bacillus subtilis. The enzyme was determined to be a serine protease based on inhibition by PMSF. Biochemical characterization demonstrated that the enzyme had optimal activity under alkaline conditions (pH 8–10). In addition, the enzyme had an elevated optimum temperature (60°C). The protease was also stable in the presence of many surfactants and oxidant. Thus, the C. proteolyticus protease has potential applications in industries such as the detergent market.
PMCID: PMC3886229  PMID: 24453843
7.  Underlying Cause and Place of Death Among Patients With Amyotrophic Lateral Sclerosis in Taiwan: A Population-Based Study, 2003–2008 
Journal of Epidemiology  2013;23(6):424-428.
Few studies have assessed cause of death among patients with amyotrophic lateral sclerosis (ALS). We investigated underlying cause and place of death among patients with ALS in Taiwan during 2003–2008.
The data source was the Taiwan National Health Insurance database for the period 2003–2008. In total, 751 patients older than 15 years with a primary diagnosis of ALS were included and followed until 2008 in the national mortality database. Crude mortality rates (per 100 person-years) and standardized mortality ratios (SMRs) were calculated in relation to cause of death, sex, and age group (15–44, 45–64, 65+ years).
In total, 297 (39.6%) patients died during the follow-up period, an age- and sex-standardized mortality rate 13 times (95% CI, 10.6–15.6) that of the Taiwanese general population. The leading cause of death among the patients was respiratory diseases, and the second most frequent cause was cardiovascular diseases. During the first year after an ALS diagnosis, suicide was much more frequent (SMR, 6.9; 95% CI, 1.9–17.6) than among the general population.
During 2003–2008, respiratory diseases and cardiovascular diseases were the most frequent causes of death among Taiwanese patients with ALS. In addition, our findings indicate that suicide prevention is an urgent priority during the period soon after an ALS diagnosis.
PMCID: PMC3834279  PMID: 23933623
amyotrophic lateral sclerosis; cause of death; respiratory disease; suicide
8.  Congenital Diaphragmatic Hernia Interval on Chromosome 8p23.1 Characterized by Genetics and Protein Interaction Networks 
Chromosome 8p23.1 is a common hotspot associated with major congenital malformations, including congenital diaphragmatic hernia (CDH) and cardiac defects. We present findings from high-resolution arrays in patients who carry a loss (n =18) or a gain (n =1) of sub-band 8p23.1. We confirm a region involved in both diaphragmatic and heart malformations. Results from a novel CNVConnect algorithm, prioritizing protein–protein interactions between products of genes in the 8p23.1 hotspot and products of previously known CDH causing genes, implicated GATA4, NEIL2, and SOX7 in diaphragmatic defects. Sequence analysis of these genes in 226 chromosomally normal CDH patients, as well as in a small number of deletion 8p23.1 patients, showed rare unreported variants in the coding region; these may be contributing to the diaphragmatic phenotype. We also demonstrated that two of these three genes were expressed in the E11.5–12.5 primordial mouse diaphragm, the developmental stage at which CDH is thought to occur. This combination of bioinformatics and expression studies can be applied to other chromosomal hotspots, as well as private microdeletions or microduplications, to identify causative genes and their interaction networks.
PMCID: PMC3761361  PMID: 23165946
congenital diaphragmatic hernia; congenital heart defect; DNA copy number variants; deletion 8p23 1; duplication 8p23 1; CNVConnect; GATA4; SOX7; NEIL2
9.  Cross-Species Array Comparative Genomic Hybridization Identifies Novel Oncogenic Events in Zebrafish and Human Embryonal Rhabdomyosarcoma 
PLoS Genetics  2013;9(8):e1003727.
Human cancer genomes are highly complex, making it challenging to identify specific drivers of cancer growth, progression, and tumor maintenance. To bypass this obstacle, we have applied array comparative genomic hybridization (array CGH) to zebrafish embryonal rhabdomyosaroma (ERMS) and utilized cross-species comparison to rapidly identify genomic copy number aberrations and novel candidate oncogenes in human disease. Zebrafish ERMS contain small, focal regions of low-copy amplification. These same regions were commonly amplified in human disease. For example, 16 of 19 chromosomal gains identified in zebrafish ERMS also exhibited focal, low-copy gains in human disease. Genes found in amplified genomic regions were assessed for functional roles in promoting continued tumor growth in human and zebrafish ERMS – identifying critical genes associated with tumor maintenance. Knockdown studies identified important roles for Cyclin D2 (CCND2), Homeobox Protein C6 (HOXC6) and PlexinA1 (PLXNA1) in human ERMS cell proliferation. PLXNA1 knockdown also enhanced differentiation, reduced migration, and altered anchorage-independent growth. By contrast, chemical inhibition of vascular endothelial growth factor (VEGF) signaling reduced angiogenesis and tumor size in ERMS-bearing zebrafish. Importantly, VEGFA expression correlated with poor clinical outcome in patients with ERMS, implicating inhibitors of the VEGF pathway as a promising therapy for improving patient survival. Our results demonstrate the utility of array CGH and cross-species comparisons to identify candidate oncogenes essential for the pathogenesis of human cancer.
Author Summary
Cancer is a complex genetic disease that is often associated with regional gains and losses of genomic DNA segments. These changes result in aberrant gene expression and drive continued tumor growth. Because amplified and deleted DNA segments tend to span large regions of chromosomes, it has been challenging to identify the genes that are required for continued tumor growth and progression. Array comparative genomic hybridization (array CGH) is an effective technology in identifying abnormal copy number variations in cancer genomes. In this study, array CGH was used in a zebrafish model of embryonal rhabdomyosarcoma - a pediatric muscle tumor. Our work shows that the zebrafish cancer genome contains a small number of recurrent DNA copy number changes, which are also commonly amplified in the human disease. Moreover, these chromosomal regions are small, facilitating rapid identification of candidate oncogenes. A subset of genes identified in zebrafish array CGH was prioritized for functional characterization in human ERMS, identifying evolutionarily conserved pathways that regulate proliferation, migration, differentiation, and neovascularization. Our results demonstrate the broad utility of cross-species array CGH comparisons of human and zebrafish cancer and provide a much needed discovery platform for identifying critical cancer-causing genes in a wide range of malignancies.
PMCID: PMC3757044  PMID: 24009521
10.  Intracortical convergence of layer 6 neurons 
Neuroreport  2012;23(12):736-740.
Axonal branches from a subset of neurons in cerebral cortical layer 6 innervate both cortical layer 4 and the thalamus. As such, these neurons are poised to modulate thalamocortical transmission at multiple forebrain sites. Here, we examined the functional organization of the layer 6 intracortical projections in auditory, somatosensory and visual cortical areas using an optogenetic approach to specifically target these neurons. We characterized the anatomical and physiological organization of these projections using laser-scanning photostimulation to functionally map the elicited postsynaptic responses in layer 4. We found that these responses originated from regions over 1 mm in width, eliciting short-term facilitating responses. These results indicate that intracortical modulation of layer 4 occurs via widespread layer 6 projections in each sensory cortical area.
PMCID: PMC3462588  PMID: 22776905
cortex; thalamus; layer 6; layer 4; optogenetics; cre-lox recombination; auditory; somatosensory; visual
11.  Diffuse flow environments within basalt- and sediment-based hydrothermal vent ecosystems harbor specialized microbial communities 
Hydrothermal vents differ both in surface input and subsurface geochemistry. The effects of these differences on their microbial communities are not clear. Here, we investigated both alpha and beta diversity of diffuse flow-associated microbial communities emanating from vents at a basalt-based hydrothermal system along the East Pacific Rise (EPR) and a sediment-based hydrothermal system, Guaymas Basin. Both Bacteria and Archaea were targeted using high throughput 16S rRNA gene pyrosequencing analyses. A unique aspect of this study was the use of a universal set of 16S rRNA gene primers to characterize total and diffuse flow-specific microbial communities from varied deep-sea hydrothermal environments. Both surrounding seawater and diffuse flow water samples contained large numbers of Marine Group I (MGI) Thaumarchaea and Gammaproteobacteria taxa previously observed in deep-sea systems. However, these taxa were geographically distinct and segregated according to type of spreading center. Diffuse flow microbial community profiles were highly differentiated. In particular, EPR dominant diffuse flow taxa were most closely associated with chemolithoautotrophs, and off axis water was dominated by heterotrophic-related taxa, whereas the opposite was true for Guaymas Basin. The diversity and richness of diffuse flow-specific microbial communities were strongly correlated to the relative abundance of Epsilonproteobacteria, proximity to macrofauna, and hydrothermal system type. Archaeal diversity was higher than or equivalent to bacterial diversity in about one third of the samples. Most diffuse flow-specific communities were dominated by OTUs associated with Epsilonproteobacteria, but many of the Guaymas Basin diffuse flow samples were dominated by either OTUs within the Planctomycetes or hyperthermophilic Archaea. This study emphasizes the unique microbial communities associated with geochemically and geographically distinct hydrothermal diffuse flow environments.
PMCID: PMC3721025  PMID: 23898323
diffuse flow; microbial diversity; 16S rRNA; pyrosequencing; hydrothermal vents
12.  Multiple Sclerosis Incidence Associated with the Soil Lead and Arsenic Concentrations in Taiwan 
PLoS ONE  2013;8(6):e65911.
Few studies in the world have assessed the incidence of multiple sclerosis (MS) with soil heavy metal concentrations. We explored the association of soil heavy metal factors and the MS incidence in Taiwan.
There were 1240 new MS cases from the National Health Insurance Research Database and were verified with serious disabling disease certificates, 1997–2008. Soil heavy metal factors records included arsenic, mercury, cadmium, chromium, copper, nickel, lead and zinc in Taiwan from 1986 to 2002. Spatial regression was used to reveal the association of soil heavy metals and age- and gender-standardized incidence ratios for townships by controlling sunlight exposure hours, smoking prevalence and spatial autocorrelation.
The lead (Pb) concentration in the soil positively correlated with the township incidence; on the other hand, the arsenic (As) concentration in soil negatively correlated with the township incidence and when found together controlled each other. The positive correlation of lead (Pb) predominated in males, whereas the negative correlation of arsenic (As) in soil predominated in females.
We conclude that exposure to lead (Pb) in soil positive associated with incidence of MS in Taiwan, especially in males. Exposure to arsenic (As) in soil negative associated with MS in Taiwan, especially in females.
PMCID: PMC3684615  PMID: 23799061
13.  Exploring the role of copy number variants in human adaptation 
Trends in genetics : TIG  2012;28(6):245-257.
Over the past decade, the ubiquity of copy number variants (CNVs, the gain or loss of genomic material) in the genomes of healthy humans has become apparent. Although some of these variants are associated with disorders, a handful of studies documented an adaptive advantage conferred by CNVs. In this review, we propose that CNVs are substrates for human evolution and adaptation. We discuss the possible mechanisms and evolutionary processes in which CNVs are selected, outline the current challenges in identifying these loci, and highlight that copy number variable regions allow for the creation of novel genes that may diversify the repertoire of such genes in response to rapidly changing environments. We expect that many more adaptive CNVs will be discovered in the coming years, and we believe that these new findings will contribute to our understanding of human-specific phenotypes.
PMCID: PMC3533238  PMID: 22483647
copy number variation; adaptation; human evolution
14.  Landscape of Somatic Retrotransposition in Human Cancers 
Science (New York, N.Y.)  2012;337(6097):967-971.
Transposable elements (TEs) are abundant in the human genome, and some are capable of generating new insertions through RNA intermediates. In cancer, the disruption of cellular mechanisms that normally suppress TE activity may facilitate mutagenic retrotranspositions. We performed single-nucleotide resolution analysis of TE insertions in 43 high-coverage whole-genome sequencing data sets from five cancer types. We identified 194 high-confidence somatic TE insertions, as well as thousands of polymorphic TE insertions in matched normal genomes. Somatic insertions were present in epithelial tumors but not in blood or brain cancers. Somatic L1 insertions tend to occur in genes that are commonly mutated in cancer, disrupt the expression of the target genes, and are biased toward regions of cancer-specific DNA hypomethylation, highlighting their potential impact in tumorigenesis.
PMCID: PMC3656569  PMID: 22745252
15.  Copy number variation genotyping using family information 
BMC Bioinformatics  2013;14:157.
In recent years there has been a growing interest in the role of copy number variations (CNV) in genetic diseases. Though there has been rapid development of technologies and statistical methods devoted to detection in CNVs from array data, the inherent challenges in data quality associated with most hybridization techniques remains a challenging problem in CNV association studies.
To help address these data quality issues in the context of family-based association studies, we introduce a statistical framework for the intensity-based array data that takes into account the family information for copy-number assignment. The method is an adaptation of traditional methods for modeling SNP genotype data that assume Gaussian mixture model, whereby CNV calling is performed for all family members simultaneously and leveraging within family-data to reduce CNV calls that are incompatible with Mendelian inheritance while still allowing de-novo CNVs. Applying this method to simulation studies and a genome-wide association study in asthma, we find that our approach significantly improves CNV calls accuracy, and reduces the Mendelian inconsistency rates and false positive genotype calls. The results were validated using qPCR experiments.
In conclusion, we have demonstrated that the use of family information can improve the quality of CNV calling and hopefully give more powerful association test of CNVs.
PMCID: PMC3668900  PMID: 23656838
16.  The Inter-Valley Soil Comparative Survey: the ecology of Dry Valley edaphic microbial communities 
The ISME Journal  2011;6(5):1046-1057.
Recent applications of molecular genetics to edaphic microbial communities of the McMurdo Dry Valleys and elsewhere have rejected a long-held belief that Antarctic soils contain extremely limited microbial diversity. The Inter-Valley Soil Comparative Survey aims to elucidate the factors shaping these unique microbial communities and their biogeography by integrating molecular genetic approaches with biogeochemical analyses. Although the microbial communities of Dry Valley soils may be complex, there is little doubt that the ecosystem's food web is relatively simple, and evidence suggests that physicochemical conditions may have the dominant role in shaping microbial communities. To examine this hypothesis, bacterial communities from representative soil samples collected in four geographically disparate Dry Valleys were analyzed using molecular genetic tools, including pyrosequencing of 16S rRNA gene PCR amplicons. Results show that the four communities are structurally and phylogenetically distinct, and possess significantly different levels of diversity. Strikingly, only 2 of 214 phylotypes were found in all four valleys, challenging a widespread assumption that the microbiota of the Dry Valleys is composed of a few cosmopolitan species. Analysis of soil geochemical properties indicated that salt content, alongside altitude and Cu2+, was significantly correlated with differences in microbial communities. Our results indicate that the microbial ecology of Dry Valley soils is highly localized and that physicochemical factors potentially have major roles in shaping the microbiology of ice-free areas of Antarctica. These findings hint at links between Dry Valley glacial geomorphology and microbial ecology, and raise previously unrecognized issues related to environmental management of this unique ecosystem.
PMCID: PMC3329106  PMID: 22170424
Antarctica; Dry Valleys; geochemistry; mineral soil
17.  Intrinsic modulators of auditory thalamocortical transmission 
Hearing Research  2012;287(1-2):43-50.
Neurons in layer 4 of the primary auditory cortex receive convergent glutamatergic inputs from thalamic and cortical projections that activate different groups of postsynaptic glutamate receptors. Of particular interest in layer 4 neurons are the Group II metabotropic glutamate receptors (mGluRs), which hyperpolarize neurons postsynaptically via the downstream opening of GIRK channels. This pronounced effect on membrane conductance could influence the neuronal processing of synaptic inputs, such as those from the thalamus, essentially modulating information flow through the thalamocortical pathway. To examine how Group II mGluRs affect thalamocortical transmission, we used an in vitro slice preparation of the auditory thalamocortical pathways in the mouse to examine synaptic transmission under conditions where Group II mGluRs were activated. We found that both pre- and post-synaptic Group II mGluRs are involved in the attenuation of thalamocortical EPSP/Cs. Thus, thalamocortical synaptic transmission is suppressed via the presynaptic reduction of thalamocortical neurotransmitter release and the postsynaptic inhibition of the layer 4 thalamorecipient neurons. This could enable the thalamocortical pathway to autoregulate transmission, via either a gating or gain control mechanism, or both.
PMCID: PMC3383630  PMID: 22726616
18.  Balancing Selection on a Regulatory Region Exhibiting Ancient Variation That Predates Human–Neandertal Divergence 
PLoS Genetics  2013;9(4):e1003404.
Ancient population structure shaping contemporary genetic variation has been recently appreciated and has important implications regarding our understanding of the structure of modern human genomes. We identified a ∼36-kb DNA segment in the human genome that displays an ancient substructure. The variation at this locus exists primarily as two highly divergent haplogroups. One of these haplogroups (the NE1 haplogroup) aligns with the Neandertal haplotype and contains a 4.6-kb deletion polymorphism in perfect linkage disequilibrium with 12 single nucleotide polymorphisms (SNPs) across diverse populations. The other haplogroup, which does not contain the 4.6-kb deletion, aligns with the chimpanzee haplotype and is likely ancestral. Africans have higher overall pairwise differences with the Neandertal haplotype than Eurasians do for this NE1 locus (p<10−15). Moreover, the nucleotide diversity at this locus is higher in Eurasians than in Africans. These results mimic signatures of recent Neandertal admixture contributing to this locus. However, an in-depth assessment of the variation in this region across multiple populations reveals that African NE1 haplotypes, albeit rare, harbor more sequence variation than NE1 haplotypes found in Europeans, indicating an ancient African origin of this haplogroup and refuting recent Neandertal admixture. Population genetic analyses of the SNPs within each of these haplogroups, along with genome-wide comparisons revealed significant FST (p = 0.00003) and positive Tajima's D (p = 0.00285) statistics, pointing to non-neutral evolution of this locus. The NE1 locus harbors no protein-coding genes, but contains transcribed sequences as well as sequences with putative regulatory function based on bioinformatic predictions and in vitro experiments. We postulate that the variation observed at this locus predates Human–Neandertal divergence and is evolving under balancing selection, especially among European populations.
Author Summary
Natural selection shapes the genome in a non-random way, as an allele that contributes more to the reproductive fitness of a species increases in frequency within the population. Under balancing selection, a particular kind of natural selection, more than one allele increases in frequency in the population, likely due to a reproductive advantage of individuals carrying both alleles. Only a handful of loci have been well documented to evolve under balancing selection, with the HBB gene (sickle cell locus) being the best studied. Here, we report a non-coding (but putatively functional) locus that has maintained two divergent alleles in the human population since before the Human–Neandertal divergence and is therefore likely to be under balancing selection. These findings also provide a clear example for ancient African substructure.
PMCID: PMC3623772  PMID: 23593015
19.  Epidemiology and Clinical Characteristics of Congenital Hypothyroidism in an Asian Population: A Nationwide Population-Based Study 
Journal of Epidemiology  2013;23(2):85-94.
The incidence of congenital hypothyroidism (CH) has been increasing in Western countries, and some populations, including Asians, have a higher incidence. Delayed diagnosis and early treatment influence the outcome of CH. We investigated the incidence and clinical characteristics of CH in Taiwan.
In this retrospective database study we identified cases of CH diagnosed during 1997–2008 in the Taiwan National Health Insurance Research Database (NHIRD). Patients who had a Serious Accidents and Diseases certificate were included in the incidence calculation. We focused on CH patients who were born during 1997–2003 and determined their age at diagnosis and CH-related clinical features. Mental retardation and physiological delays were evaluated with respect to age at diagnosis.
A total of 1482 cases were identified. Incidence during the 12-year period was 5.02 per 10 000 births. Among 1115 patients, the most common clinical features of CH were developmental delay (9.6%), constipation (11.6%), and delayed physiological development (9.1%). Congenital anomalies of the heart (7.7%), epilepsy (2.7%), and infantile cerebral palsy (3.2%) were also noted. Survival analysis showed that the risks of mental retardation (hazard ratio [HR], 3.180) and delayed physiological development (HR, 1.908) were greater when age at diagnosis was greater than 1 year.
CH incidence was higher in Taiwan than in Western countries. Early diagnosis may decrease the risk of mental and physiological delay.
PMCID: PMC3700243  PMID: 23291568
congenital hypothyroidism; epidemiology; early diagnosis
20.  Comparison of Familial and Sporadic Chronic Lymphocytic Leukaemia Using High Resolution Array Comparative Genomic Hybridization 
British journal of haematology  2010;151(4):336-345.
Approximately 10% of patients with chronic lymphocytic leukaemia (CLL) have a family history of the disease or a related lymphoproliferative disorder, yet the relationship of familial CLL to genomic abnormalities has not been characterized in detail. We therefore studied 75 CLL patients, half familial and half sporadic, using high-resolution array comparative genomic hybridization (CGH), in order to better define the relationship of genomic abnormalities to familial disease and other biological prognostic factors. Our results showed that the most common high-risk deletion in CLL, deletion 11q, was significantly associated with sporadic disease. Comparison of familial to sporadic disease additionally identified a copy number variant region near the centromere on 14q, proximal to IGH@, in which gains were associated both with familial CLL, and with mutated IGHV and homozygous deletion of 13q. Homozygous deletion of 13q was also found to be associated with mutated IGHV and low expression of ZAP-70, and a significantly longer time to first treatment compared to heterozygous deletion or lack of alteration. This study is the first high resolution effort to investigate and report somatic genetic differences between familial and sporadic CLL.
PMCID: PMC3584328  PMID: 20812997
CLL; familial; deletion 11q
21.  Riluzole and Prognostic Factors in Amyotrophic Lateral Sclerosis Long-term and Short-term Survival: A Population-Based Study of 1149 Cases in Taiwan 
Journal of Epidemiology  2013;23(1):35-40.
Amyotrophic lateral sclerosis (ALS) is a rare disease in Taiwan; thus, estimation of ALS mortality is difficult. We evaluated factors associated with ALS survival in Taiwan.
The study enrolled 1149 Taiwanese with a primary diagnosis of ALS during 1999–2008. Follow-up information was available for all patients; mean (SD) duration of follow-up was 2.91 (2.62) years. Medical interventions, including noninvasive positive pressure ventilation (NIPPV), tracheotomy, gastrostomy, and riluzole, were included in time-dependent survival analysis.
Of the 1149 ALS patients, 438 (38.12%) died during follow-up. Mortality in the first year was 16%, which was 13 times (95% CI 11.1–15.2) the age- and sex-standardized rate of the general population in Taiwan. The average annual crude mortality rate was 13.1% (person-years). Factors significantly associated with increased mortality were male sex, advanced age, rural residence, lower economic status, no tracheotomy, and no riluzole treatment. Significant predictors of long-term versus average survival were younger age at diagnosis, being a dependent or receiving social welfare, and NIPPV support. Significant predictors of short-term versus average survival were older age, being employed, no tracheotomy, and no riluzole use.
The results support the use of riluzole to improve ALS survival. Patients who received riluzole and underwent tracheotomy had the best survival.
PMCID: PMC3700231  PMID: 23117224
amyotrophic lateral sclerosis; survival; riluzole; tracheotomy
22.  Evolutionary genetics of the human Rh blood group system 
Human genetics  2012;131(7):1205-1216.
The evolutionary history of variation in the human Rh blood group system, determined by variants in the RHD and RHCE genes, has long been an unresolved puzzle in human genetics. Prior to medical treatments and interventions developed in the last century, the D-positive children of D-negative women were at risk for hemolytic disease of the newborn, if the mother produced anti-D antibodies following sensitization to the blood of a previous D-positive child. Given the deleterious fitness consequences of this disease, the appreciable frequencies in European populations of the responsible RHD gene deletion variant (for example, 0.43 in our study) seem surprising. In this study, we used new molecular and genomic data generated from four HapMap population samples to test the idea that positive selection for an as-of-yet unknown fitness benefit of the RHD deletion may have offset the otherwise negative fitness effects of hemolytic disease of the newborn. We found no evidence that positive natural selection affected the frequency of the RHD deletion. Thus, the initial rise to intermediate frequency of the RHD deletion in European populations may simply be explained by genetic drift/ founder effect, or by an older or more complex sweep that we are insufficiently powered to detect. However, our simulations recapitulate previous findings that selection on the RHD deletion is frequency dependent, and weak or absent near 0.5. Therefore, once such a frequency was achieved, it could have been maintained by a relatively small amount of genetic drift. We unexpectedly observed evidence for positive selection on the C allele of RHCE in non-African populations (on chromosomes with intact copies of the RHD gene) in the form of an unusually high FST value and the high frequency of a single haplotype carrying the C allele. RhCE function is not well understood, but the C/c antigenic variant is clinically relevant and can result in hemolytic disease of the newborn, albeit much less commonly and severely than that related to the D-negative blood type. Therefore, the potential fitness benefits of the RHCE C allele are currently unknown but merit further exploration.
PMCID: PMC3378649  PMID: 22367406
Blood group polymorphism; copy number variation; human evolution; balancing selection
23.  Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration 
Nature genetics  2012;44(4):390-S1.
We defined the genetic landscape of balanced chromosomal rearrangements at nucleotide resolution by sequencing 141 breakpoints from cytogenetically-interpreted translocations and inversions. We confirm that the recently described phenomenon of “chromothripsis” (massive chromosomal shattering and reorganization) is not unique to cancer cells but also occurs in the germline where it can resolve to a karyotypically balanced state with frequent inversions. We detected a high incidence of complex rearrangements (19.2%) and substantially less reliance on microhomology (31%) than previously observed in benign CNVs. We compared these results to experimentally-generated DNA breakage-repair by sequencing seven transgenic animals, and revealed extensive rearrangement of the transgene and host genome with similar complexity to human germline alterations. Inversion is the most common rearrangement, suggesting that a combined mechanism involving template switching and non-homologous repair mediates the formation of balanced complex rearrangements that are viable, stably replicated and transmitted unaltered to subsequent generations.
PMCID: PMC3340016  PMID: 22388000
25.  A murine lung cancer co–clinical trial identifies genetic modifiers of therapeutic response 
Nature  2012;483(7391):613-617.
Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers1–4. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy1,3. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors5–9, has not been fully explored. Here we use genetically engineered mouse models to conduct a ‘co-clinical’ trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244)10 increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors6,9,11,12, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.
PMCID: PMC3385933  PMID: 22425996

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