Human Congenital Diseases with Mixed Modes of Inheritance Have a Shortage of Recessive Disease. A Demographic Scenario?
|
|
- Lauren Gilbert
- 5 years ago
- Views:
Transcription
1 doi: /j x Human Congenital Diseases with Mixed Modes of Inheritance Have a Shortage of Recessive Disease. A Demographic Scenario? N. Avrion Mitchison 1, Shomi Bhattacharya 1 and Edward G. D. Tuddenham 2 1 Institute of Ophthalmology, University College London (UCL), Bath St, London EC1V 9EL, UK 2 Research Department of Hematology, Royal Free Hospital, Pond Street, London NW3 2QG, UK Summary An archive of congenital human diseases is presented, aiming to contain all those where recessive (biallelic) can be compared with X-linked and/or dominant (monoallelic) inheritance. A significant deficit of recessive inheritance is evident, both in disease inheritance and in contribution to inheritance per known disease gene. The deficit contrasts with expectation derived from the cell biology of mutation, and from the importance of recessive mutation in evolution and its preponderance in N-ethyl-N-nitrosourea (ENU) mutagenesis. The deficit fits well with the standard model of demographic change since the neolithic era, and may also reflect natural selection acting on heterozygotes. Keywords: Inheritance, X-linked, recessive, dominant, demography, selection Introduction The modes of inheritance of congenital disease are worth examining from an evolutionary perspective, because the influence of natural selection on the recessive (AR) mode of inheritance is so different from that on X-linked (XL) and dominant (AD) modes. For congenital disease, the recessive mutations are likely to circulate for longer periods in the human population, with profound effects evident in the higher single nucleotide polymorphism (SNP) ratio (Dn/Ds, the ratio of nonsynonymous to synonymous nucleotide substitution) of recessive disease genes (Furney et al., 2006, Blekhman et al., 2008). The disease frequencies would also be expected to differ with AR disease inheritance being more deeply influenced by demographic change (Williamson et al., 2005) and by natural selection operating on heterozygotes. The problem with testing these predictions is that the population frequency of the different modes of inheritance is seldom known accurately. Accordingly, we here take the narrower approach of comparing the relative frequency of the modes within those diseases where the AR form of a disease can be compared with its AD and/or XL forms. Such data are regularly kept Corresponding author: N. Avrion Mitchison, Institute of Ophthalmology, University College London (UCL), Bath St, London EC1V 9EL, UK. Tel.: / ; E- mail: n.mitchison@ucl.ac.uk for each disease because of their importance for diagnosis and for assessing risk to family members. We have assembled an archive of diseases that have the necessary mix of inheritance modes, together with lead references, in a form that allows addition of new data and corrections. The archive is based on a search through Online Mendelian Inheritance in Man (OMIM), screened for a suitable assortment of inheritance modes, and is presented in supporting information. Various smaller data sets based on OMIM have been assembled for other purposes such as calculation of the SNP ratio or the mutation rate. To avoid ascertainment bias, we included all the available data for diseases with mixed inheritance mode. As these data vary in quality, we identified a subset of diseases where the mode of inheritance has been analysed more thoroughly. These selected data were then analysed and compared with the total data set. The two data sets, selected and total, turn out to provide concordant evidence of a shortage of recessive disease. The shortage observed applies to inheritance of the disease, as well as to inheritance per gene (i.e. per known recessive gene compared with per known dominant or XL gene). Discarding other explanations such as a lower rate of recessive mutation, we propose that passage of the European population through a demographic bottleneck best explains this shortage. The present archive has features in common with the Orphanet collection of prevalence data for rare diseases (Orphanet Report Series, 2010). We cite below the valuable 688 Annals of Human Genetics (2011) 75, C 2011 The Authors
2 Distribution of Modes of Inheritance data from this collection, although these do not readily allow the frequency of the modes of inheritance to be compared within a disease. We hope that our archive will attract critical scrutiny, made easier by the alphabetic arrangement. The corresponding author would be grateful for corrections and pointers to additional good quality data. Materials and Methods The archive presented here in supporting information lists data for 95 diseases assembled as follows. The OMIM database (assembled by the National Center for Biotechnology Information, Bethesda, MD) currently lists 2867 diseases with phenotype description and molecular basis known, of which 692 (24%) include recessive AND (dominant OR XL). We searched this list for entries for the archive, using the following criteria. Data excluded were as follows: (i) redundant entries, where a single disease has several entries (e.g. dominant and recessive forms entered separately), as is usual in OMIM; (ii) entries with only a single gene, which has both dominant and recessive mutations; (iii) association studies (excluded because they do not identify modes of inheritance); (iv) entries listed only because they mention dominant and/or recessive forms of XL disease; (v) nondisease entries such as pigmentation or frizzled hair. We counted only genes with a known chromosomal location, which are usually listed under the OMIM entry title. These criteria excluded 597 OMIM entries, leaving 95 entered into the present archive, which is presented here in supporting information. As mentioned below, we have not yet sorted out the contribution from isolated populations, where the frequency of recessive disease alleles is expected to be relatively high. Our analysis omits consideration of disease alleles identified solely by genome sequencing (Vissers et al., 2010). The archive is arranged in columns with the diseases listed in alphabetic order with their OMIM numbers and a lead citation. The following three columns show the % inheritance of the disease found in the three modes of inheritance (XL, AR and AD). The last three columns show the number of genes identified as responsible for the disease in each mode. Thus, for example, retinitis pigementosa is present in 10% of patients as XL, 36% as recessive and 54% as dominant disease. Of the known causal genes, 2 are XL, 26 are recessive and 12 are dominant. The median population frequency of the diseases in the archive is Data for the proportions of inheritance and the number of genes (and in some cases their date of discovery) were acquired from the lead citations listed in the archive and from other published data. To avoid selection bias, no disease was excluded for lack of information. We evaluated the data as shown in the first column of the archive, where an asterisk denotes the 16 diseases that have the most substantial data. The category includes a range of four each immunological and musculoskeletal, two each ophthalmological, haematological and neurological, and one each sensory and renal disease. The data come from national (OMIM numbers , , , , ) and international (118220, , , , , , ) surveys, and from single large (>60 patients) clinical series (120970, , , ). Categorizing the data in this way allows the analysis of the diseases with the best data to be compared with the full data set. Fortunately, the two data sets yield similar findings, as presented below. Results First, to gain an overview of how the acquisition of data is progressing, we traced the accumulation of mutation in the six representative diseases, as shown in Figure 1. They show how accumulation has progressed over the last two decades, and suggest that it has slowed for XL mutations and is beginning to slow for AR and AD mutations. The earlier accumulation of XL data is as expected from their easier ascertainment. Thus, the distribution of the modes of inheritance is now clear enough to merit attention, although no doubt likely to require revision in the future. In the archived data, we first compared the 22 diseases where AR > AD inheritance with the 57 where AR < AD. The difference is highly significant p = (Fisher s exact contingency test). However, the corresponding comparison of AR with XL inheritance does not show a significant difference. We next compared the contributions to disease frequency from AD, AR and XL inheritance, and also the contributions to disease frequency per known mutation of each type, with results shown in Figure 2. The two charts refer to the total archived data on the left (95 diseases) and the right to the more substantial data, graded (16 diseases). In both groups, the % disease inheritance and the % inheritance per known gene are significantly lower for both the AR disease inheritance and the number of AR genes, as compared with either the XL or AD diseases and genes (eight comparisons, in each case with p < 0.05). The % inheritance per recessive gene has been multiplied by two, to allow for the two recessive genes lost per disease case. This correction was applied in the comparisons, as shown in Figure 2. The % inheritance per recessive gene is particularly low for the better data set (right-hand panel). This reflects the fact that this set has, on average, twice as many recessive genes per disease. Evidently, diseases with large numbers of mutations attract more systematic work, as might be expected. Allowing the two data C 2011 The Authors Annals of Human Genetics (2011) 75,
3 N. A. Mitchison et al. Figure 1 Progressive accumulation of mutations in six representative diseases. Figure 2 Distribution of inheritance between the three modes within the diseases surveyed: showing mean and standard error of mean. The left-hand panel refers to the total archived data (95 diseases), and the right to the 16 diseases with best data, graded as showninthearchive. White bars: % inheritance per disease. Black bars: % inheritance per known gene, doubled for AR genes to allow for two genes per disease case. sets to be compared (total versus more substantial) reduces the likelihood of undetected ascertainment bias. The analysis thus yields a clear shortage of recessive inheritance in congenital disease, in a collection that contains most of the data at present available. Discussion In considering the shortage of recessive inheritance found here, we can first dispose of the misconception that recessive inheritance is less common simply because each new mutation 690 Annals of Human Genetics (2011) 75, C 2011 The Authors
4 Distribution of Modes of Inheritance lingers in the human population before it meets another. This could not explain the low equilibrium level of recessive disease. We do not here consider quantitative variation in disease impact, for simplicity and because the age of onset of congenital disease has little influence on the Dn/Ds ratio (Blekhman et al., 2008). The recessive mutation rate in man is not intrinsically low (Lynch, 2010), and mutations are dominant only in the restricted circumstances of haploinsufficiency or gainof-function. Hence, a higher frequency of recessive disease mutations might be expected. Early mutagenesis studies in mice, in fact, confirmed this expectation (Ehling et al., 1985), as have later large-scale studies of N-ethyl-N-nitrosourea (ENU) mutagenesis in mice (Cook et al., 2006, Nelms & Goodnow, 2001, Jamsai & O Bryan, 2010). The ENU community worldwide is largely moving over to screening only for recessive mutations. Against this background, the shortage of recessive inheritance found in the present study requires explanation. Demographic change since the ice age era provides a plausible explanation as follows. The two population coalescence models identify a bottleneck in the European population during the last ice age and before the start of agriculture, when expansion began (Schaffner et al., 2005, Williamson et al., 2005, Reich & Lander, 2001). Inbreeding depression mediated by purging of recessive disease mutations would have occurred during the bottleneck. Loss of deleterious recessive alleles in this way has been observed in many species, and mathematical models have been developed (Charlesworth & Willis, 2009). An early application was to a bottleneck in the Japanese population (Nei & Imaizumi, 1963). We have applied this modelling as follows. The median disease frequency in our collection is , to which each AR disease allele contributes an average of 10.2%. The AR disease frequency per allele then is , with a corresponding allele frequency in the population of ( ) = We assume that entry of the disease allele into the population by mutation (μ) and exit by disease are in balance at a rate of per generation. This rate is in line with previous estimates of μ, such as the rate arrived at after survey of several earlier estimates (Reich & Lander, 2001). We further assume that a recessive disease allele accumulates during recovery from purging in the bottleneck at a rate of μ per generation (neglecting temporarily the loss of disease alleles through disease that is discussed below). We make the arbitrary assumption that purging reduces the disease frequency by 50%, and thus allows recovery to start from a median disease frequency per allele of The Williamson et al. s estimate allows 900 generations of recovery (Williamson et al., 2005). With our estimated value of μ, these assumptions would allow the disease allele frequency in the population to recover up to a present-day level of , a little less than the present equilibrium estimate of , and thus well able to account for the deficit in AR inheritance, as shown in Figure 2. The selected group of better documented diseases has the same median frequency of , but has more recessive genes for each disease, so that each gene contributes an average of only 4.6% of the disease. Recovery in the model is therefore less complete, in accordance with the larger deficit in AR inheritance evident in Figure 2. So far, the calculation accounts for entry of AR disease genes during recovery from the bottleneck, but not for loss through disease (i.e. loss-through-homozygosis). We examined recovery in a spreadsheet-based model similar to that used previously (Testa & Bojarski, 2007). We increase the frequency of the AR disease allele by a factor of μ 2μ 2 in each successive generation (μ for entry by mutation, 2μ 2 for loss-through-homozygosis at Hardy-Weinberg equilibrium, as shown in Figure 3. Evidently, this simple loss-throughhomozygosis model works reasonably well for values of μ in the range of ( ). We then asked how this relates to the values of μ found (as prevalence) in the Orphanet survey (Orphanet Report Series, 2010), where we found 31 diseases from our archive listed with their prevalence, which we take as estimates of μ. Of these diseases, 14 had values of μ that fell within the range of , indicating that the model fits the available data reasonably well. However, the four diseases in this sample that had values of over do call for some adjustment of the model. As is well known, natural selection may also operate on the heterozygote of disease alleles classified as recessive. The general pattern is of slightly deleterious carrier effects, but with beneficial effects also widely reported, for instance, among genes involved in resistance to infection (Dean et al., 2002). The panel of diseases in the present narrow archive would not be particularly useful for evaluating this form of natural selection, where a genome-wide approach would be more appropriate. Finally, we need to consider alternative explanations for the shortage of recessives. One concerns the outcome of recent large population association studies, which seems only to identify near-additive effects although this can partly be explained by incomplete LD diminishing the dominance/recessive effect and a bias of researchers to only look for additive effects. Recent population expansion and perhaps more outbreeding with more mobility may have increased our carrying capacity for recessive alleles. Furthermore, the more important bottleneck for non-africans dates back to the time of emergence of our ancestors from Africa perhaps kya. The more recent ice age may not have provided a bottleneck severe enough to eliminate the signals of earlier expansion in the interglacial period roughly kya. C 2011 The Authors Annals of Human Genetics (2011) 75,
5 N. A. Mitchison et al. Figure 3 Recovery over 900 generations of a recessive disease gene that had been fully purged during a bottleneck. New mutations accumulate linearly (dashed lines) if no allowance is made for their loss through expression in homozygotes. The three panels show the effect of loss through expression in homozygotes for mutations occurring at the three rates (μ) (solid lines). A second possible explanation for the shortage of recessive forms concerns their relative level of severity. High severity could reduce the population frequency by hindering spread of a mutant gene, as has been proposed for retinal degeneration where the most severe form, Leber congenital amaurosis (involving many genes), is also the commonest. We have not yet examined the impact of disease timing and severity on recessive gene frequency. Clearly, the diseases in the present archive would provide suitable material for evaluating this possibility, but this would be a large task requiring care to avoid data-selective bias. Another factor tending to reduce the frequency of recessive forms is their loss in isolated populations. This is certainly the case, but again, we have not yet managed to sort out the effect. The effect of consanguinity is also likely to be important. It would be of interest, for example, to compare the recessive disease frequency in North versus South India. In conclusion, a significant shortage of recessive inheritance has been identified, which we suggest may reflect in part at least demographic change in the human population. Acknowledgements We thank D. Isaacs and G. Clark for setting up the spreadsheet model used here, D. Balding (UCL) for discussion of recent large-scale association studies and early demography, and R. P. Erickson (University of Arizona) for mentioning the importance of disease severity. References Blekhman, R., Man, O., Herrmann, L., Boyko, A. R., Indap, A., Kosiol, C., Bustamante, C. D., Teshima, K. M. & Przeworski, M. (2008) Natural selection on genes that underlie human disease susceptibility. Curr Biol 18, Charlesworth, D. & Willis, J. H. (2009) The genetics of inbreeding depression. Nat Rev Genet 10, Cook, M. C., Vinuesa, C. G. & Goodnow, C. C. (2006) ENUmutagenesis: Insight into immune function and pathology. Curr Opin Immunol 18, Dean, M., Carrington, M. & O Brien, S. J. (2002) Balanced polymorphism selected by genetic versus infectious human disease. Annu Rev Genomics Hum Genet 3, Ehling, U. H., Charles, D. J., Favor, J., Graw, J., Kratochvilova, J., Neuhauser-Klaus, A. & Pretsch, W. (1985) Induction of gene mutations in mice: The multiple endpoint approach. Mutat Res 150, Furney, S. J., Alba, M. M. & Lopez-Bigas, N. (2006) Differences in the evolutionary history of disease genes affected by dominant or recessive mutations. BMC Genomics 7, Jamsai, D. & O Bryan, M. K. (2010) Genome-wide ENU mutagenesis for the discovery of novel male fertility regulators. Syst Biol Reprod Med 56, Lynch, M. (2010) Rate, molecular spectrum, and consequences of human mutation. Proc Natl Acad Sci USA 107, Nei, M. & Imaizumi, Y. (1963) Estimation of mutation rate in rare recessive traits. Am J Hum Genet 15, Nelms, K. A. & Goodnow, C. C. (2001) Genome-wide ENU mutagenesis to reveal immune regulators. Immunity 15, Orphanet Report Series (2010) Prevalence of rare diseases: Bibliographic data, Orphanet Report Series, Rare Diseases collection. of_rare_diseases_by_alphabetical_list.pdf. Reich, D. E. & Lander, E. S. (2001) On the allelic spectrum of human disease. Trends Genet 17, Schaffner, S. F., Foo, C., Gabriel, S., Reich, D., Daly, M. J. & Altshuler, D. (2005) Calibrating a coalescent simulation of human genome sequence variation. Genome Res 15, Testa, B. & Bojarski, A. J. (2007) Variation, natural selection, and information content A simulation. Chem Biodivers 4, Vissers, L. E., De Ligt, J., Gilissen, C., Janssen, I., Steehouwer, M., De Vries, P., Van Lier, B., Arts, P., Wieskamp, N., Del Rosario, M., Van Bon, B. W., Hoischen, A., De Vries, B. B., Brunner, H. G. & Veltman, J. A. (2010) A de novo paradigm for mental retardation. Nat Genet 42, Annals of Human Genetics (2011) 75, C 2011 The Authors
6 Distribution of Modes of Inheritance Williamson, S. H., Hernandez, R., Fledel-Alon, A., Zhu, L., Nielsen, R. & Bustamante, C. D. (2005) Simultaneous inference of selection and population growth from patterns of variation in the human genome. Proc Natl Acad Sci USA 102, Supporting Information Additional supporting information may be found in the online version of this article: As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer-reviewed and may be re-organised for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Received: 17 May 2011 Accepted: 5 August 2011 C 2011 The Authors Annals of Human Genetics (2011) 75,
A. Incorrect! Cells contain the units of genetic they are not the unit of heredity.
MCAT Biology Problem Drill PS07: Mendelian Genetics Question No. 1 of 10 Question 1. The smallest unit of heredity is. Question #01 (A) Cell (B) Gene (C) Chromosome (D) Allele Cells contain the units of
More informationCHAPTER 16 POPULATION GENETICS AND SPECIATION
CHAPTER 16 POPULATION GENETICS AND SPECIATION MULTIPLE CHOICE 1. Which of the following describes a population? a. dogs and cats living in Austin, Texas b. four species of fish living in a pond c. dogwood
More informationPopulation Genetics Simulation Lab
Name Period Assignment # Pre-lab: annotate each paragraph Population Genetics Simulation Lab Evolution occurs in populations of organisms and involves variation in the population, heredity, and differential
More informationPedigree Analysis Why do Pedigrees? Goals of Pedigree Analysis Basic Symbols More Symbols Y-Linked Inheritance
Pedigree Analysis Why do Pedigrees? Punnett squares and chi-square tests work well for organisms that have large numbers of offspring and controlled mating, but humans are quite different: Small families.
More informationCh. 23 The Evolution of Populations
Ch. 23 The Evolution of Populations 1 Essential question: Do populations evolve? 2 Mutation and Sexual reproduction produce genetic variation that makes evolution possible What is the smallest unit of
More informationBio 312, Spring 2017 Exam 3 ( 1 ) Name:
Bio 312, Spring 2017 Exam 3 ( 1 ) Name: Please write the first letter of your last name in the box; 5 points will be deducted if your name is hard to read or the box does not contain the correct letter.
More informationThe plant of the day Pinus longaeva Pinus aristata
The plant of the day Pinus longaeva Pinus aristata Today s Topics Non-random mating Genetic drift Population structure Big Questions What are the causes and evolutionary consequences of non-random mating?
More informationGenetics and Genomics in Medicine Chapter 8 Questions
Genetics and Genomics in Medicine Chapter 8 Questions Linkage Analysis Question Question 8.1 Affected members of the pedigree above have an autosomal dominant disorder, and cytogenetic analyses using conventional
More informationRoadmap. Inbreeding How inbred is a population? What are the consequences of inbreeding?
1 Roadmap Quantitative traits What kinds of variation can selection work on? How much will a population respond to selection? Heritability How can response be restored? Inbreeding How inbred is a population?
More informationHARDY- WEINBERG PRACTICE PROBLEMS
HARDY- WEINBERG PRACTICE PROBLEMS PROBLEMS TO SOLVE: 1. The proportion of homozygous recessives of a certain population is 0.09. If we assume that the gene pool is large and at equilibrium and all genotypes
More informationBio 1M: Evolutionary processes
Bio 1M: Evolutionary processes Evolution by natural selection Is something missing from the story I told last chapter? Heritable variation in traits Selection (i.e., differential reproductive success)
More informationComputational Systems Biology: Biology X
Bud Mishra Room 1002, 715 Broadway, Courant Institute, NYU, New York, USA L#4:(October-0-4-2010) Cancer and Signals 1 2 1 2 Evidence in Favor Somatic mutations, Aneuploidy, Copy-number changes and LOH
More informationSingle Gene (Monogenic) Disorders. Mendelian Inheritance: Definitions. Mendelian Inheritance: Definitions
Single Gene (Monogenic) Disorders Mendelian Inheritance: Definitions A genetic locus is a specific position or location on a chromosome. Frequently, locus is used to refer to a specific gene. Alleles are
More informationMendelian Genetics and Beyond Chapter 4 Study Prompts
Mendelian Genetics and Beyond Chapter 4 Study Prompts 1. What is a mode of inheritance? 2. Can you define the following? a. Autosomal dominant b. Autosomal recessive 3. Who was Gregor Mendel? 4. What did
More informationPrentice Hall. Biology: Concepts and Connections, 6th Edition (Campbell, et al) High School
Prentice Hall Biology: Concepts and Connections, 6th Edition (Campbell, et al) 2009 High School C O R R E L A T E D T O Biology I Students should understand that scientific knowledge is gained from observation
More informationPeer review on manuscript "Multiple cues favor... female preference in..." by Peer 407
Peer review on manuscript "Multiple cues favor... female preference in..." by Peer 407 ADDED INFO ABOUT FEATURED PEER REVIEW This peer review is written by an anonymous Peer PEQ = 4.6 / 5 Peer reviewed
More informationp and q can be thought of as probabilities of selecting the given alleles by
Lecture 26 Population Genetics Until now, we have been carrying out genetic analysis of individuals, but for the next three lectures we will consider genetics from the point of view of groups of individuals,
More informationWhat favorite organism of geneticists is described in the right-hand column?
What favorite organism of geneticists is described in the right-hand column? Model Organism fruit fly?? Generation time 12 days ~ 5000 days Size 2 mm 1500-1800mm Brood size hundreds a couple dozen would
More informationVan test naar diagnose naar
Van test naar diagnose naar V therapie op maat Marjolein Kriek, LUMC Joris Veltman, RUNMC Exome diagnostics in genetically heterogeneous disease Joris Veltman, PhD Department of Human Genetics Radboud
More informationDan Koller, Ph.D. Medical and Molecular Genetics
Design of Genetic Studies Dan Koller, Ph.D. Research Assistant Professor Medical and Molecular Genetics Genetics and Medicine Over the past decade, advances from genetics have permeated medicine Identification
More informationTwo hierarchies. Genes Chromosomes Organisms Demes Populations Species Clades
Evolution cont d Two hierarchies Genes Chromosomes Organisms Demes Populations Species Clades Molecules Cells Organisms Populations Communities Ecosystems Regional Biotas At its simplest level Evolution
More informationEvolution II.2 Answers.
Evolution II.2 Answers. 1. (4 pts) Contrast the predictions of blending inheritance for F1 and F2 generations with those observed under Mendelian inheritance. Blending inheritance predicts both F1 and
More informationIntroduction to genetic variation. He Zhang Bioinformatics Core Facility 6/22/2016
Introduction to genetic variation He Zhang Bioinformatics Core Facility 6/22/2016 Outline Basic concepts of genetic variation Genetic variation in human populations Variation and genetic disorders Databases
More informationWill now consider in detail the effects of relaxing the assumption of infinite-population size.
FINITE POPULATION SIZE: GENETIC DRIFT READING: Nielsen & Slatkin pp. 21-27 Will now consider in detail the effects of relaxing the assumption of infinite-population size. Start with an extreme case: a
More informationJay M. Baraban MD, PhD January 2007 GENES AND BEHAVIOR
Jay M. Baraban MD, PhD jay.baraban@gmail.com January 2007 GENES AND BEHAVIOR Overview One of the most fascinating topics in neuroscience is the role that inheritance plays in determining one s behavior.
More informationCharacteristics and Traits
Characteristics and Traits Inquire: Characteristics and Traits Overview Alleles do not always behave in dominant and recessive patterns. Incomplete dominance describes situations in which the heterozygote
More informationHomozygote Incidence
Am. J. Hum. Genet. 41:671-677, 1987 The Effects of Genetic Screening and Assortative Mating on Lethal Recessive-Allele Frequencies and Homozygote Incidence R. B. CAMPBELL Department of Mathematics and
More information2) Cases and controls were genotyped on different platforms. The comparability of the platforms should be discussed.
Reviewers' Comments: Reviewer #1 (Remarks to the Author) The manuscript titled 'Association of variations in HLA-class II and other loci with susceptibility to lung adenocarcinoma with EGFR mutation' evaluated
More information(b) What is the allele frequency of the b allele in the new merged population on the island?
2005 7.03 Problem Set 6 KEY Due before 5 PM on WEDNESDAY, November 23, 2005. Turn answers in to the box outside of 68-120. PLEASE WRITE YOUR ANSWERS ON THIS PRINTOUT. 1. Two populations (Population One
More informationVariant Detection & Interpretation in a diagnostic context. Christian Gilissen
Variant Detection & Interpretation in a diagnostic context Christian Gilissen c.gilissen@gen.umcn.nl 28-05-2013 So far Sequencing Johan den Dunnen Marja Jakobs Ewart de Bruijn Mapping Victor Guryev Variant
More informationTotal pathogenic allele frequency of autosomal recessive MEFV mutations causing familial Mediterranean fever in Tunisia and Morocco
CHAPTER 7 Total pathogenic allele frequency of autosomal recessive MEFV mutations causing familial Mediterranean fever in Tunisia and Morocco Teeuw ME/ Kelmemi W, Jonker MA, Kharrat M, Lariani I, Laarabi
More informationBST227 Introduction to Statistical Genetics. Lecture 4: Introduction to linkage and association analysis
BST227 Introduction to Statistical Genetics Lecture 4: Introduction to linkage and association analysis 1 Housekeeping Homework #1 due today Homework #2 posted (due Monday) Lab at 5:30PM today (FXB G13)
More informationComplex Traits Activity INSTRUCTION MANUAL. ANT 2110 Introduction to Physical Anthropology Professor Julie J. Lesnik
Complex Traits Activity INSTRUCTION MANUAL ANT 2110 Introduction to Physical Anthropology Professor Julie J. Lesnik Introduction Human variation is complex. The simplest form of variation in a population
More informationGenetics Unit Exam. Number of progeny with following phenotype Experiment Red White #1: Fish 2 (red) with Fish 3 (red) 100 0
Genetics Unit Exam Question You are working with an ornamental fish that shows two color phenotypes, red or white. The color is controlled by a single gene. These fish are hermaphrodites meaning they can
More informationTrait characteristic (hair color) Gene segment of DNA Allele a variety of a trait (brown hair or blonde hair)
Evolution Change in DNA to favor certain traits over multiple generations Adaptations happen within a single generations Evolution is the result of adding adaptations together Evolution doesn t have a
More informationPedigree Construction Notes
Name Date Pedigree Construction Notes GO TO à Mendelian Inheritance (http://www.uic.edu/classes/bms/bms655/lesson3.html) When human geneticists first began to publish family studies, they used a variety
More informationLecture 17: Human Genetics. I. Types of Genetic Disorders. A. Single gene disorders
Lecture 17: Human Genetics I. Types of Genetic Disorders A. Single gene disorders B. Multifactorial traits 1. Mutant alleles at several loci acting in concert C. Chromosomal abnormalities 1. Physical changes
More informationLaws of Inheritance. Bởi: OpenStaxCollege
Bởi: OpenStaxCollege The seven characteristics that Mendel evaluated in his pea plants were each expressed as one of two versions, or traits. Mendel deduced from his results that each individual had two
More informationEVOLUTION. Hardy-Weinberg Principle DEVIATION. Carol Eunmi Lee 9/20/16. Title goes here 1
Hardy-Weinberg Principle Hardy-Weinberg Theorem Mathematical description of Mendelian inheritance In a non-evolving population, frequency of alleles and genotypes remain constant over generations Godfrey
More informationIntroduction to the Genetics of Complex Disease
Introduction to the Genetics of Complex Disease Jeremiah M. Scharf, MD, PhD Departments of Neurology, Psychiatry and Center for Human Genetic Research Massachusetts General Hospital Breakthroughs in Genome
More informationMendelian Genetics. 7.3 Gene Linkage and Mapping Genes can be mapped to specific locations on chromosomes.
7 Extending CHAPTER Mendelian Genetics GETTING READY TO LEARN Preview Key Concepts 7.1 Chromosomes and Phenotype The chromosomes on which genes are located can affect the expression of traits. 7.2 Complex
More informationSelection at one locus with many alleles, fertility selection, and sexual selection
Selection at one locus with many alleles, fertility selection, and sexual selection Introduction It s easy to extend the Hardy-Weinberg principle to multiple alleles at a single locus. In fact, we already
More informationChapter 1 : Genetics 101
Chapter 1 : Genetics 101 Understanding the underlying concepts of human genetics and the role of genes, behavior, and the environment will be important to appropriately collecting and applying genetic
More informationLTA Analysis of HapMap Genotype Data
LTA Analysis of HapMap Genotype Data Introduction. This supplement to Global variation in copy number in the human genome, by Redon et al., describes the details of the LTA analysis used to screen HapMap
More informationMendelian Genetics. KEY CONCEPT Mendel s research showed that traits are inherited as discrete units.
KEY CONCEPT Mendel s research showed that traits are inherited as discrete units. Mendel laid the groundwork for genetics. Traits are distinguishing characteristics that are inherited. Genetics is the
More informationTHE GENETICAL THEORY OF NATURAL SELECTION
Chapter 12 THE GENETICAL THEORY OF NATURAL SELECTION Important points to remember about natural selection: 1. Natural selection is not the same as evolution. Evolution requires the origin of variation
More informationSequencing studies implicate inherited mutations in autism
NEWS Sequencing studies implicate inherited mutations in autism BY EMILY SINGER 23 JANUARY 2013 1 / 5 Unusual inheritance: Researchers have found a relatively mild mutation in a gene linked to Cohen syndrome,
More informationResearch Article Power Estimation for Gene-Longevity Association Analysis Using Concordant Twins
Genetics Research International, Article ID 154204, 8 pages http://dx.doi.org/10.1155/2014/154204 Research Article Power Estimation for Gene-Longevity Association Analysis Using Concordant Twins Qihua
More informationCh 4: Mendel and Modern evolutionary theory
Ch 4: Mendel and Modern evolutionary theory 1 Mendelian principles of inheritance Mendel's principles explain how traits are transmitted from generation to generation Background: eight years breeding pea
More informationMicroevolution Changing Allele Frequencies
Microevolution Changing Allele Frequencies Evolution Evolution is defined as a change in the inherited characteristics of biological populations over successive generations. Microevolution involves the
More information9/25/ Some traits are controlled by a single gene. Selective Breeding: Observing Heredity
Chapter 7 Learning Outcomes Explain the concept of a single-gene trait Describe Mendel s contributions to the field of genetics Be able to define the terms gene, allele, dominant, recessive, homozygous,
More informationLACTASE PERSISTENCE: EVIDENCE FOR SELECTION
LACTASE PERSISTENCE: EVIDENCE FOR SELECTION INTRODUCTION The ability of some human adults to digest lactose the sugar in milk is evidence of recent human evolution. All mammalian babies can digest lactose,
More informationChapter 21.2 Mechanisms of Evolutionary Change
Beak depth of Beak depth Colonie High AP Biology Chapter 21.2 Mechanisms of Evolutionary Change Populations Evolve! Natural selection acts on individuals differential survival survival of the fittest differential
More informationMULTIFACTORIAL DISEASES. MG L-10 July 7 th 2014
MULTIFACTORIAL DISEASES MG L-10 July 7 th 2014 Genetic Diseases Unifactorial Chromosomal Multifactorial AD Numerical AR Structural X-linked Microdeletions Mitochondrial Spectrum of Alterations in DNA Sequence
More informationSolutions to Genetics Unit Exam
Solutions to Genetics Unit Exam Question 1 You are working with an ornamental fish that shows two color phenotypes, red or white. The color is controlled by a single gene. These fish are hermaphrodites
More informationAnalysis of single gene effects 1. Quantitative analysis of single gene effects. Gregory Carey, Barbara J. Bowers, Jeanne M.
Analysis of single gene effects 1 Quantitative analysis of single gene effects Gregory Carey, Barbara J. Bowers, Jeanne M. Wehner From the Department of Psychology (GC, JMW) and Institute for Behavioral
More information7.03 Lecture 26 11/14/01
Now we are going to consider how allele frequencies change under the influence of mutation and. First, we will consider mutation. Mutation A µ a µ = q mut = Phenylketonuria (PKU) allele frequency q 0.1
More informationGENETICS - NOTES-
GENETICS - NOTES- Warm Up Exercise Using your previous knowledge of genetics, determine what maternal genotype would most likely yield offspring with such characteristics. Use the genotype that you came
More informationFor more information about how to cite these materials visit
Author(s): Kerby Shedden, Ph.D., 2010 License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution Share Alike 3.0 License: http://creativecommons.org/licenses/by-sa/3.0/
More informationHuman Genetic Diseases (Ch. 15)
Human Genetic Diseases (Ch. 15) 1 2 2006-2007 3 4 5 6 Genetic counseling Pedigrees can help us understand the past & predict the future Thousands of genetic disorders are inherited as simple recessive
More informationName Class Date. KEY CONCEPT The chromosomes on which genes are located can affect the expression of traits.
Section 1: Chromosomes and Phenotype KEY CONCEPT The chromosomes on which genes are located can affect the expression of traits. VOCABULARY carrier sex-linked gene X chromosome inactivation MAIN IDEA:
More informationUnifactorial or Single Gene Disorders. Hanan Hamamy Department of Genetic Medicine and Development Geneva University Hospital
Unifactorial or Single Gene Disorders Hanan Hamamy Department of Genetic Medicine and Development Geneva University Hospital Training Course in Sexual and Reproductive Health Research Geneva 2011 Single
More informationBiology 12. Mendelian Genetics
Mendelian Genetics Genetics: the science (study) of heredity that involves the structure and function of genes and the way genes are passed from one generation to the next. Heredity: the passing on of
More informationTEACHER S GUIDE. Case Study. Lactose tolerance. Steve Cross, Bronwyn Terrill and colleagues. Wellcome Trust Sanger Institute Hinxton. Version 1.
TEACHER S GUIDE Case Study Lactose tolerance Version 1.1 Steve Cross, Bronwyn Terrill and colleagues Wellcome Trust Sanger Institute Hinxton Lactose tolerance The majority of people living today are unable
More informationIS IT GENETIC? How do genes, environment and chance interact to specify a complex trait such as intelligence?
1 IS IT GENETIC? How do genes, environment and chance interact to specify a complex trait such as intelligence? Single-gene (monogenic) traits Phenotypic variation is typically discrete (often comparing
More informationProposal form for the evaluation of a genetic test for NHS Service Gene Dossier
Proposal form for the evaluation of a genetic test for NHS Service Gene Dossier Test Disease Population Triad Disease name Leber congenital amaurosis OMIM number for disease 204000 Disease alternative
More informationThe Six Ws of DNA testing A scenario-based activity introducing medical applications of DNA testing
The Six Ws of DNA testing A scenario-based activity introducing medical applications of DNA testing Overview This activity introduces a number of different ways that genetic tests can be used in medicine.
More informationB-4.7 Summarize the chromosome theory of inheritance and relate that theory to Gregor Mendel s principles of genetics
B-4.7 Summarize the chromosome theory of inheritance and relate that theory to Gregor Mendel s principles of genetics The Chromosome theory of inheritance is a basic principle in biology that states genes
More informationLearning Outcomes: The following list provides the learning objectives that will be covered in the lectures, and tutorials of each week:
Course Code Course Title ECTS Credits MED-306 Medical Genetics 6 School Semester Prerequisites Medical School Spring (Semester 6) MED-103 Biology I MED-109 Biology II MED-204 Biochemistry I MED-209 Biochemistry
More informationThe Law of Segregation Introduction Today, we know that many of people's characteristics, from hair color to height to risk of diabetes, are
The Law of Segregation Introduction Today, we know that many of people's characteristics, from hair color to height to risk of diabetes, are influenced by genes. We also know that genes are the way parents
More informationCITATION FILE CONTENT/FORMAT
CITATION For any resultant publications using please cite: Matthew A. Field, Vicky Cho, T. Daniel Andrews, and Chris C. Goodnow (2015). "Reliably detecting clinically important variants requires both combined
More information- Aya Alomoush. - Talal Al-Zabin. - Belal Azab. 1 P a g e
24 - Aya Alomoush - Talal Al-Zabin - Belal Azab 1 P a g e 1) Features of autosomal dominant inheritance: A) Vertical transmission: direct transmission from grandparent to parent to child without skipping
More informationmouse, which show a combination of unusual properties. The
EFFECT OF X-RAYS ON THE MUTATION OF t-alleles IN THE MOUSE MARY F. LYON M.R.C. Radiobio!ogica! Research Unit, Harwell, Berkshire Received 18.ix.59 1.!NTRODUCTtON THE t-alleles are a long series of recessive
More informationGaucher disease 3/22/2009. Mendelian pedigree patterns. Autosomal-dominant inheritance
Mendelian pedigree patterns Autosomal-dominant inheritance Autosomal dominant Autosomal recessive X-linked dominant X-linked recessive Y-linked Examples of AD inheritance Autosomal-recessive inheritance
More informationMeiotic Mistakes and Abnormalities Learning Outcomes
Meiotic Mistakes and Abnormalities Learning Outcomes 5.6 Explain how nondisjunction can result in whole chromosomal abnormalities. (Module 5.10) 5.7 Describe the inheritance patterns for strict dominant
More informationPsych 3102 Lecture 3. Mendelian Genetics
Psych 3102 Lecture 3 Mendelian Genetics Gregor Mendel 1822 1884, paper read 1865-66 Augustinian monk genotype alleles present at a locus can we identify this? phenotype expressed trait/characteristic can
More informationNeutral evolution in colorectal cancer, how can we distinguish functional from non-functional variation?
in partnership with Neutral evolution in colorectal cancer, how can we distinguish functional from non-functional variation? Andrea Sottoriva Group Leader, Evolutionary Genomics and Modelling Group Centre
More informationWhen bad things happen to good genes: mutation vs. selection
When bad things happen to good genes: mutation vs. selection Selection tends to increase the frequencies of alleles with higher marginal fitnesses. Does this mean that genes are perfect? No, mutation can
More informationHuman Molecular Genetics Prof. S. Ganesh Department of Biological Sciences and Bioengineering Indian Institute of Technology, Kanpur
Human Molecular Genetics Prof. S. Ganesh Department of Biological Sciences and Bioengineering Indian Institute of Technology, Kanpur Module - 02 Lecture - 06 Let us test your understanding of Pedigree
More informationInbreeding and Inbreeding Depression
Inbreeding and Inbreeding Depression Inbreeding is mating among relatives which increases homozygosity Why is Inbreeding a Conservation Concern: Inbreeding may or may not lead to inbreeding depression,
More informationYES NO UNKNOWN PENETRANCE ACTIONABILITY SIGNIFICANCE/BURDEN OF DISEASE NEXT STEPS. YES (Proceed to Stage II) YES ( 1 of above)
Stage I: Rule-Out Dashboard GENE/GENE PANEL: ATP7B DISORDER: Wilson Disease HGNC ID: 870 OMIM ID: 277900 ACTIONABILITY 1. Is there a qualifying resource, such as a practice guideline or systematic review,
More informationMicroevolution: The Forces of Evolutionary Change Part 2. Lecture 23
Microevolution: The Forces of Evolutionary Change Part 2 Lecture 23 Outline Conditions that cause evolutionary change Natural vs artificial selection Nonrandom mating and sexual selection The role of chance
More informationHow Organisms Evolve Chapters The Theory of Evolution. The Theory of Evolution. Evolution can be traced through the fossil record.
How Organisms Evolve Chapters 14-15 The Theory of Evolution Evolution is the process of change in the inherited traits of a population of organisms from one generation to the next. The inherited traits
More informationSEX. Genetic Variation: The genetic substrate for natural selection. Sex: Sources of Genotypic Variation. Genetic Variation
Genetic Variation: The genetic substrate for natural selection Sex: Sources of Genotypic Variation Dr. Carol E. Lee, University of Wisconsin Genetic Variation If there is no genetic variation, neither
More informationLab 5: Testing Hypotheses about Patterns of Inheritance
Lab 5: Testing Hypotheses about Patterns of Inheritance How do we talk about genetic information? Each cell in living organisms contains DNA. DNA is made of nucleotide subunits arranged in very long strands.
More informationPunne% Square Quiz A AP Tes2ng this week 15-Week Grades due next week Note: media center is hos2ng tes2ng Turn in all make-up work
Biology Monday, May 2, 2016 Do-Now: Punne% Square Quiz A 1. Write down today s FLT 2. What do we use Punne@ Squares for? 3. A purple flower (Pp) and a white flower are crossed. What % of the offspring
More informationOMIM The Online Mendelian Inheritance in Man Knowledgebase: A Wardrobe Full of Genes. Ada Hamosh, MD, MPH
OMIM The Online Mendelian Inheritance in Man Knowledgebase: A Wardrobe Full of Genes Ada Hamosh, MD, MPH OMIM THE ONLINE MENDELIAN INHERITANCE IN MAN KNOWLEDGEBASE: A WARDROBE FULL OF GENES The OMIM knowledgebase
More informationA gene is a sequence of DNA that resides at a particular site on a chromosome the locus (plural loci). Genetic linkage of genes on a single
8.3 A gene is a sequence of DNA that resides at a particular site on a chromosome the locus (plural loci). Genetic linkage of genes on a single chromosome can alter their pattern of inheritance from those
More informationUnit 5 Review Name: Period:
Unit 5 Review Name: Period: 1 4 5 6 7 & give an example of the following. Be able to apply their meanings: Homozygous Heterozygous Dominant Recessive Genotype Phenotype Haploid Diploid Sex chromosomes
More informationUNIT III (Notes) : Genetics : Mendelian. (MHR Biology p ) Traits are distinguishing characteristics that make a unique individual.
1 UNIT III (Notes) : Genetics : endelian. (HR Biology p. 526-543) Heredity is the transmission of traits from one generation to another. Traits that are passed on are said to be inherited. Genetics is
More informationA MILESTONE IN GENETICS: Mendel s 1866 Paper
A MILESTONE IN GENETICS: Mendel s 1866 Paper The paper that launched the science of genetics had the title Versuche über Pflanzenhybriden which translates from the German as Experiments with Plant-Hybrids.
More informationAsingle inherited mutant gene may be enough to
396 Cancer Inheritance STEVEN A. FRANK Asingle inherited mutant gene may be enough to cause a very high cancer risk. Single-mutation cases have provided much insight into the genetic basis of carcinogenesis,
More informationThe consequences of not accounting for background selection in demographic inference
Molecular Ecology (2015) doi: 10.1111/mec.13390 SPECIAL ISSUE: DETECTING SELECTION IN NATURAL POPULATIONS: MAKING SENSE OF GENOME SCANS AND TOWARDS ALTERNATIVE SOLUTIONS The consequences of not accounting
More informationLabrador Coat Color Similar to coat color in mice: Black lab is BxEx Yellow lab is xxee Chocolate lab is bbex Probable pathway:
Honors Genetics 1. Gregor Mendel (1822-1884) German monk at the Augustine Abbey of St. Thomas in Brno (today in the Czech Republic). He was a gardener, teacher and priest. Mendel conducted experiments
More informationBasic Definitions. Dr. Mohammed Hussein Assi MBChB MSc DCH (UK) MRCPCH
Basic Definitions Chromosomes There are two types of chromosomes: autosomes (1-22) and sex chromosomes (X & Y). Humans are composed of two groups of cells: Gametes. Ova and sperm cells, which are haploid,
More informationOverview of Animal Breeding
Overview of Animal Breeding 1 Required Information Successful animal breeding requires 1. the collection and storage of data on individually identified animals; 2. complete pedigree information about the
More informationSystems of Mating: Systems of Mating:
8/29/2 Systems of Mating: the rules by which pairs of gametes are chosen from the local gene pool to be united in a zygote with respect to a particular locus or genetic system. Systems of Mating: A deme
More informationTumor suppressor genes D R. S H O S S E I N I - A S L
Tumor suppressor genes 1 D R. S H O S S E I N I - A S L What is a Tumor Suppressor Gene? 2 A tumor suppressor gene is a type of cancer gene that is created by loss-of function mutations. In contrast to
More informationWhat is the inheritance pattern (e.g., autosomal, sex-linked, dominant, recessive, etc.)?
Module I: Introduction to the disease Give a brief introduction to the disease, considering the following: the symptoms that define the syndrome, the range of phenotypes exhibited by individuals with the
More informationPre-AP Biology Unit 7 Genetics Review Outline
Unit 7 Genetics Review Outline Pre-AP Biology 2017-2018 LT 1 - I can explain the relationships among alleles, genes, chromosomes, genotypes, and phenotypes. This target covers application of the vocabulary
More information