Gene duplication is an important source of phenotypic change and adaptive evolution. We leverage a haploid hydatidiform mole to identify highly identical sequences missing from the reference genome, ...confirming that the cortical development gene Slit-Robo Rho GTPase-activating protein 2 (SRGAP2) duplicated three times exclusively in humans. We show that the promoter and first nine exons of SRGAP2 duplicated from 1q32.1 (SRGAP2A) to 1q21.1 (SRGAP2B) ∼3.4 million years ago (mya). Two larger duplications later copied SRGAP2B to chromosome 1p12 (SRGAP2C) and to proximal 1q21.1 (SRGAP2D) ∼2.4 and ∼1 mya, respectively. Sequence and expression analyses show that SRGAP2C is the most likely duplicate to encode a functional protein and is among the most fixed human-specific duplicate genes. Our data suggest a mechanism where incomplete duplication created a novel gene function—antagonizing parental SRGAP2 function—immediately “at birth” 2–3 mya, which is a time corresponding to the transition from Australopithecus to Homo and the beginning of neocortex expansion.
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► Missing SRGAP2 human-specific genes sequenced by using haploid hydatidiform mole DNA ► SRGAP2 duplicated three times in the human lineage ∼1.0–3.4 million years ago ► One duplicate is expressed in the brain and is fixed in copy number in all humans ► The incomplete initial duplication likely antagonized the parent gene at birth
A series of incomplete duplications of an ancestral neuronal gene that took place only in the human lineage generated truncated genes, likely to encode new functions immediately upon “birth.” The appearance of these human-specific genes coincides with the emergence of an expanded neocortex.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Birds are essential components of most ecosystems and provide many services valued by society. However, many populations have undergone striking declines as their habitats have been lost or degraded ...by human activities. Terrestrial grasslands are vital habitat for birds in the North American Prairie Pothole Region (PPR), but grassland conversion and fragmentation from agriculture and energy-production activities have destroyed or degraded millions of hectares. Conservation grasslands can provide alternate habitat. In the United States, the Conservation Reserve Program (CRP) is the largest program maintaining conservation grasslands on agricultural lands, but conservation grasslands in the PPR have declined by over 1 million ha since the program's zenith in 2007. We used an ecosystem-services model (InVEST) parameterized for the PPR to quantify grassland-bird habitat remaining in 2014 and to assess the degradation status of the remaining grassland-bird habitat as influenced by crop and energy (i.e., oil, natural gas, and wind) production. We compared our resultant habitat-quality ratings to grassland-bird abundance data from the North American Breeding Bird Survey to confirm that ratings were related to grassland-bird abundance. Of the grassland-bird habitat remaining in 2014, about 19% was degraded by crop production that occurred within 0.1 km of grassland habitats, whereas energy production degraded an additional 16%. We further quantified the changes in availability of grassland-bird habitat under various land-cover scenarios representing incremental losses (10%, 25%, 50%, 75%, and 100%) of CRP grasslands from 2014 levels. Our model identified 1 million ha (9%) of remaining grassland-bird habitat in the PPR that would be lost or degraded if all CRP conservation grasslands were returned to crop production. Grassland regions world-wide face similar challenges in maintaining avian habitat in the face of increasing commodity and energy production to sate the food and energy needs of a growing world population. Identifying ways to model the impacts of the tradeoff between food and energy production and wildlife production is an important step in creating solutions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although an increasing number of copy-number variations are being identified as susceptibility loci for a variety of pediatric diseases, the penetrance of these copy-number variations remains mostly ...unknown. This poses challenges for counseling, both for recurrence risks and prenatal diagnosis. We sought to provide empiric estimates for penetrance for some of these recurrent, disease-susceptibility loci.
We conducted a Bayesian analysis, based on the copy-number variation frequencies in control populations (n = 22,246) and in our database of >48,000 postnatal microarray-based comparative genomic hybridization samples. The background risk for congenital anomalies/developmental delay/intellectual disability was assumed to be ~5%. Copy-number variations studied were 1q21.1 proximal duplications, 1q21.1 distal deletions and duplications, 15q11.2 deletions, 16p13.11 deletions, 16p12.1 deletions, 16p11.2 proximal and distal deletions and duplications, 17q12 deletions and duplications, and 22q11.21 duplications.
Estimates for the risk of an abnormal phenotype ranged from 10.4% for 15q11.2 deletions to 62.4% for distal 16p11.2 deletions.
This model can be used to provide more precise estimates for the chance of an abnormal phenotype for many copy-number variations encountered in the prenatal setting. By providing the penetrance, additional, critical information can be given to prospective parents in the genetic counseling session.
Genet Med 2013:15(6):478–481
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To understand the genetic heterogeneity underlying developmental delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) ...to CNVs in 8,329 unaffected adult controls. We estimate that ∼14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of developmental delay, intellectual disability and autism spectrum disorders.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The contribution of renewable energy to meet worldwide demand continues to grow. Wind energy is one of the fastest growing renewable sectors, but new wind facilities are often placed in prime ...wildlife habitat. Long‐term studies that incorporate a rigorous statistical design to evaluate the effects of wind facilities on wildlife are rare. We conducted a before‐after‐control‐impact (BACI) assessment to determine if wind facilities placed in native mixed‐grass prairies displaced breeding grassland birds. During 2003–2012, we monitored changes in bird density in 3 study areas in North Dakota and South Dakota (U.S.A.). We examined whether displacement or attraction occurred 1 year after construction (immediate effect) and the average displacement or attraction 2–5 years after construction (delayed effect). We tested for these effects overall and within distance bands of 100, 200, 300, and >300 m from turbines. We observed displacement for 7 of 9 species. One species was unaffected by wind facilities and one species exhibited attraction. Displacement and attraction generally occurred within 100 m and often extended up to 300 m. In a few instances, displacement extended beyond 300 m. Displacement and attraction occurred 1 year after construction and persisted at least 5 years. Our research provides a framework for applying a BACI design to displacement studies and highlights the erroneous conclusions that can be made without the benefit of adopting such a design. More broadly, species‐specific behaviors can be used to inform management decisions about turbine placement and the potential impact to individual species. Additionally, the avoidance distance metrics we estimated can facilitate future development of models evaluating impacts of wind facilities under differing land‐use scenarios.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or ...related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.
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▸ Mechanisms of epigenetic and transcriptional regulation implicated in autism ▸ Balanced chromosomal abnormality breakpoints harbor individual strong-effect genes ▸ Dosage-sensitive loci confer risk to autism from a spectrum of mutational mechanisms ▸ Different alterations in a gene are associated with diverse clinical outcomes
Sequencing of balanced chromosomal abnormalities, combined with convergent genomic studies of gene expression, copy-number variation, and genome-wide association, identifies 22 new loci that contribute to autism and related neurodevelopmental disorders. These data support a polygenic risk model for autism and provide new insight into how different types of mutations of the same genes can lead to variable disease phenotypes that manifest at different stages of life.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The McMurdo Dry Valleys of Antarctica experience a range of selective pressures, including extreme seasonal variation in temperature, water and nutrient availability, and UV radiation. Microbial mats ...in this ecosystem harbor dense concentrations of biomass in an otherwise desolate environment. Microbial inhabitants must mitigate these selective pressures
specialized enzymes, changes to the cellular envelope, and the production of secondary metabolites, such as pigments and osmoprotectants. Here, we describe the isolation and characterization of a Gram-negative, rod-shaped, motile, red-pigmented bacterium, strain DJPM01, from a microbial mat within the Don Juan Pond Basin of Wright Valley. Analysis of strain DJMP01's genome indicates it can be classified as a member of the
species. The genome contains several genes associated with cold and salt tolerance, including multiple RNA helicases, protein chaperones, and cation/proton antiporters. In addition, we identified 17 putative secondary metabolite gene clusters, including a number of nonribosomal peptides and ribosomally synthesized and post-translationally modified peptides (RiPPs), among others, and the biosynthesis pathway for the antimicrobial pigment prodigiosin. When cultivated on complex agar, multiple prodiginines, including the antibiotic prodigiosin, 2-methyl-3-propyl-prodiginine, 2-methyl-3-butyl-prodiginine, 2-methyl-3-heptyl-prodiginine, and cycloprodigiosin, were detected by LC-MS. Genome analyses of sequenced members of the
genus indicates prodigiosin production is unique to Antarctic strains. UV-A radiation, an ecological stressor in the Antarctic, was found to significantly decrease the abundance of prodiginines produced by strain DJPM01. Genomic and phenotypic evidence indicates strain DJPM01 can respond to the ecological conditions of the DJP microbial mat, with prodiginines produced under a range of conditions, including extreme UV radiation.
In the past decade, we have witnessed a flood of reports about mutations that cause or contribute to intellectual disability (ID). This rapid progress has been driven in large part by the ...implementation of chromosomal microarray analysis and next-generation sequencing methods. The findings have revealed extensive genetic heterogeneity for ID, as well as examples of a common genetic etiology for ID and other neurobehavioral/psychiatric phenotypes. Clinical diagnostic application of these new findings is already well under way, despite incomplete understanding of non-Mendelian transmission patterns that are sometimes observed.
Translocation of chromosomes can result in disruption of genes. In this case report, a sequencing approach was used to identify the cause and effect of a translocation within 13 days, a period ...consistent with use of the approach in prenatal diagnosis.
Deep sequencing of the whole genome holds diagnostic promise but is currently thought to be impractical for routine prenatal care. In contrast, large-insert mate-pair, or jumping-library, sequencing provides a tractable approach for immediate clinical application and could complement conventional prenatal diagnostics. The risk of major structural birth defects among live births in the United States is approximately 3%
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and is associated with inherited or de novo genetic rearrangements and mutations as well as with maternal factors, such as advanced age, certain clinical conditions, and exposure to teratogenic factors. Approximately 1 in 2000 prenatal cases analyzed with conventional karyotyping has a . . .
The nonsense-mediated mRNA decay (NMD) pathway functions not only to degrade transcripts containing premature termination codons (PTC), but also to regulate the transcriptome. UPF3B and RBM8A, ...important components of NMD, have been implicated in various forms of intellectual disability (ID) and Thrombocytopenia with Absent Radius (TAR) syndrome, which is also associated with ID. To gauge the contribution of other NMD factors to ID, we performed a comprehensive search for copy number variants (CNVs) of 18 NMD genes among individuals with ID and/or congenital anomalies. We identified 11 cases with heterozygous deletions of the genomic region encompassing UPF2, which encodes for a direct interacting protein of UPF3B. Using RNA-Seq, we showed that the genome-wide consequence of reduced expression of UPF2 is similar to that seen in patients with UPF3B mutations. Out of the 1009 genes found deregulated in patients with UPF2 deletions by at least 2-fold, majority (95%) were deregulated similarly in patients with UPF3B mutations. This supports the major role of deletion of UPF2 in ID. Furthermore, we found that four other NMD genes, UPF3A, SMG6, EIF4A3 and RNPS1 are frequently deleted and/or duplicated in the patients. We postulate that dosage imbalances of these NMD genes are likely to be the causes or act as predisposing factors for neuro-developmental disorders. Our findings further emphasize the importance of NMD pathway(s) in learning and memory.
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