Genetics Commons^™

The Genetic Ancestry Of African Americans, Latinos, And European Americans Across The United States, Katarzyna Bryc, Eric Y. Durand, J. Michael Macpherson, David Reich, Joanna Mountain

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Over the past 500 years, North America has been the site of ongoing mixing of Native Americans, European settlers, and Africans (brought largely by the trans-Atlantic slave trade), shaping the early history of what became the United States. We studied the genetic ancestry of 5,269 self-described African Americans, 8,663 Latinos, and 148,789 European Americans who are 23andMe customers and show that the legacy of these historical interactions is visible in the genetic ancestry of present-day Americans. We document pervasive mixed ancestry and asymmetrical male and female ancestry contributions in all groups studied. We show that regional ancestry differences reflect historical …

Haplotype Variety Analysis Of Human Populations: An Application To Hapmap Data, Michelle Creek, Cyril Rakovski

e-Research: A Journal of Undergraduate Work

We undertake a study to investigate the haplotype variety of distinct human populations. We use a natural measure of haplotype variety, the total number of haplotypes (TNH) present that reflects the number of haplotypes with nonzero frequencies estimated from the data at hand for each selection of multiple loci. For the analysis of real human populations, we use the haplotype data of the Denver Chinese, Tuscan Italians, Luhya Kenyans, and Gujarati Indians from release III of the HapMap database. Moreover, we show that the TNH statistic is biased in small sample data scenarios such as the HapMap and implement a …

On The Ranking Of The Disease Susceptibility Locus In Family-Based Candidate Gene Studies: A Simulation-Based Analysis, Lisa A. Brown, Cyril Rakovski

e-Research: A Journal of Undergraduate Work

The ranking of the p-value of the true causal single nucleotide polymorphism in the ordered list of individual SNP p-values is an important factor for achieving success in the ultimate objective of association studies - identifying deleterious genetic variants. Thus, we undertake a study to assess the implications of complex, multimarker correlation structure, sample size and disease models on the ranking of the causal SNP. We carry out an extensive family-based candidate gene simulation study to analyze the position of the disease susceptibility locus in the complete list of individual SNP p-values ordered according to their statistical significance. We simulate …

Sma-Causing Missense Mutations In Survival Motor Neuron (Smn) Display A Wide Range Of Phenotypes When Modeled In Drosophila, Kavita Praveen, Ying Wen, Kelsey M. Gray, John J. Noto, Akash R. Patlolla, Gregory D. Van Duyne, A. Gregory Matera

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Mutations in the human survival motor neuron 1 (SMN) gene are the primary cause of spinal muscular atrophy (SMA), a devastating neuromuscular disorder. SMN protein has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), core components of the spliceosome. Additional tissue-specific and global functions have been ascribed to SMN; however, their relevance to SMA pathology is poorly understood and controversial. Using Drosophila as a model system, we created an allelic series of twelve Smn missense mutations, originally identified in human SMA patients. We show that animals expressing these SMA-causing mutations display a broad range of …

Resolution By Unassisted Top3 Points To Template Switch Recombination Intermediates During Dna Replication, M. Rebecca Glineburg, Alejandro Chavez, Vishesh Agrawal, Steven J. Brill, F. Brad Johnson

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The evolutionarily conserved Sgs1/Top3/Rmi1 (STR) complex plays vital roles in DNA replication and repair. One crucial activity of the complex is dissolution of toxic X-shaped recombination intermediates that accumulate during replication of damaged DNA. However, despite several years of study the nature of these X-shaped molecules remains debated. Here we use genetic approaches and two-dimensional gel electrophoresis of genomic DNA to show that Top3, unassisted by Sgs1 and Rmi1, has modest capacities to provide resistance to MMS and to resolve recombination-dependent X-shaped molecules. The X-shaped molecules have structural properties consistent with hemicatenane-related template switch recombination intermediates (Rec-Xs) but not Holliday …

Higher Il-6 And Il6:Igf Ratio In Patients With Barth Syndrome, Lori D. Wilson, Sadeeka Al-Majid, Cyril Rakovski, Christina D. Schwindt

Mathematics, Physics, and Computer Science Faculty Articles and Research

Background: Barth Syndrome (BTHS) is a serious X-linked genetic disorder associated with mutations in the tafazzin gene (TAZ, also called G4.5). The multi-system disorder is primarily characterized by the following pathologies: cardiac and skeletal myopathies, neutropenia, growth delay, and exercise intolerance. Although growth anomalies have been widely reported in BTHS, there is a paucity of research on the role of inflammation and the potential link to alterations in growth factors levels in BTHS patients.

Methods: Plasma from 36 subjects, 22 patients with Barth Syndrome (0.5 - 24 yrs) and 14 healthy control males (8 - 21 yrs) was …

Cryptic Distant Relatives Are Common In Both Isolated And Cosmopolitan Genetic Samples, Brenna M. Henn, Lawrence S. Hon, J. Michael Macpherson, Nicholas Eriksson, Serge Saxonov, Itsik Pe'er, Joanna Mountain

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Although a few hundred single nucleotide polymorphisms (SNPs) suffice to infer close familial relationships, high density genome-wide SNP data make possible the inference of more distant relationships such as 2nd to 9th cousinships. In order to characterize the relationship between genetic similarity and degree of kinship given a timeframe of 100–300 years, we analyzed the sharing of DNA inferred to be identical by descent (IBD) in a subset of individuals from the 23andMe customer database (n = 22,757) and from the Human Genome Diversity Panel (HGDP-CEPH, n = 952). With data from 121 populations, we show that the average amount …

Efficient Replication Of Over 180 Genetic Associations With Self-Reported Medical Data, Joyce Y. Tung, Chuong B. Do, David A. Hinds, Amy K. Kiefer, J. Michael Macpherson, Arnab B. Chowdry, Uta Francke, Brian Naughton, Joanna Mountain, Anne Wojcicki, Nicholas Eriksson

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

While the cost and speed of generating genomic data have come down dramatically in recent years, the slow pace of collecting medical data for large cohorts continues to hamper genetic research. Here we evaluate a novel online framework for obtaining large amounts of medical information from a recontactable cohort by assessing our ability to replicate genetic associations using these data. Using web-based questionnaires, we gathered self-reported data on 50 medical phenotypes from a generally unselected cohort of over 20,000 genotyped individuals. Of a list of genetic associations curated by NHGRI, we successfully replicated about 75% of the associations that we …

Web-Based, Participant-Driven Studies Yield Novel Genetic Associations For Common Traits, Nicholas Eriksson, J. Michael Macpherson, Joyce Y. Tung, Lawrence S. Hon, Brian Naughton, Serge Saxonov, Linda Avey, Anne Wojcicki, Itsik Pe'er, Joanna Mountain

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Despite the recent rapid growth in genome-wide data, much of human variation remains entirely unexplained. A significant challenge in the pursuit of the genetic basis for variation in common human traits is the efficient, coordinated collection of genotype and phenotype data. We have developed a novel research framework that facilitates the parallel study of a wide assortment of traits within a single cohort. The approach takes advantage of the interactivity of the Web both to gather data and to present genetic information to research participants, while taking care to correct for the population structure inherent to this study design. Here …

High Rate Of Recent Transposable Element–Induced Adaptation In Drosophila Melanogaster, Josefa Gonzalez, Kapa Lenkov, Mikhail Lipatov, J. Michael Macpherson, Dmitri A. Petrov

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Although transposable elements (TEs) are known to be potent sources of mutation, their contribution to the generation of recent adaptive changes has never been systematically assessed. In this work, we conduct a genome-wide screen for adaptive TE insertions in Drosophila melanogaster that have taken place during or after the spread of this species out of Africa. We determine population frequencies of 902 of the 1,572 TEs in Release 3 of the D. melanogaster genome and identify a set of 13 putatively adaptive TEs. These 13 TEs increased in population frequency sharply after the spread out of Africa. We argue that …

Similar Levels Of X-Linked And Autosomal Nucleotide Variation In African And Non-African Populations Of Drosophila Melanogaster, Nadia D. Singh, J. Michael Macpherson, Jeffrey D. Jensen, Dmitri A. Petrov

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Background: Levels of molecular diversity in Drosophila have repeatedly been shown to be higher in ancestral, African populations than in derived, non-African populations. This pattern holds for both coding and noncoding regions for a variety of molecular markers including single nucleotide polymorphisms and microsatellites. Comparisons of X-linked and autosomal diversity have yielded results largely dependent on population of origin.

Results: In an attempt to further elucidate patterns of sequence diversity in Drosophila melanogaster, we studied nucleotide variation at putatively nonfunctional X-linked and autosomal loci in sub-Saharan African and North American strains of D. melanogaster. We combine our experimental …

Flavin Charge Transfer Transitions Assist Dna Photolyase Electron Transfer, Spiros S. Skourtis, Tatiana Prytkova, David Beratan

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

This contribution describes molecular dynamics, semi-empirical and ab-initio studies of the primary photo-induced electron transfer reaction in DNA photolyase. DNA photolyases are FADH−-containing proteins that repair UV-damaged DNA by photo-induced electron transfer. A DNA photolyase recognizes and binds to cyclobutatne pyrimidine dimer lesions of DNA. The protein repairs a bound lesion by transferring an electron to the lesion from FADH−, upon photo-excitation of FADH− with 350–450 nm light. We compute the lowest singlet excited states of FADH− in DNA photolyase using INDO/S configuration interaction, time-dependent density-functional, and time-dependent Hartree-Fock methods. The calculations identify the lowest singlet excited state of FADH− …

Coupling Coherence Distinguishes Structure Sensitivity In Protein Electron Transfer, Tatiana Prytkova, Igor V. Kurnikov, David Beratan

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Quantum mechanical analysis of electron tunneling in nine thermally fluctuating cytochrome b562 derivatives reveals two distinct protein-mediated coupling limits. A structure-insensitive regime arises for redox partners coupled through dynamically averaged multiple-coupling pathways (in seven of the nine derivatives) where heme-edge coupling leads to the multiple-pathway regime. A structure-dependent limit governs redox partners coupled through a dominant pathway (in two of the nine derivatives) where axial-ligand coupling generates the single-pathway limit and slower rates. This two-regime paradigm provides a unified description of electron transfer rates in 26 ruthenium-modified heme and blue-copper proteins, as well as in numerous photosynthetic proteins.

Demographic Estimates From Y Chromosome Microsatellite Polymorphisms: Analysis Of A Worldwide Sample, J. Michael Macpherson, Sohini Ramachandran, Lisa Diamond, Marcus W. Feldman

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Polymorphisms in microsatellites on the human Y chromosome have been used to estimate important demographic parameters of human history. We compare two coalescent-based statistical methods that give estimates for a number of demographic parameters using the seven Y chromosome polymorphisms in the HGDP-CEPH Cell Line Panel, a collection of samples from 52 worldwide populations. The estimates for the time to the most recent common ancestor vary according to the method used and the assumptions about the prior distributions of model parameters, but are generally consistent with other global Y chromosome studies. We explore the sensitivity of these results to assumptions …