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More complications to Mendel Complications to the relationship between genotype to phenotype Commentary written in response to the release of the first draft of the human genome sequence From Science Compass August 3, 2001 • Human genome sequencing will reveal thousands of genetic variations among individuals that many will assume are associated with disease or phenotypic variation • But translating such genotypic differences into phenotypic states is prone to pitfalls • for example, genetic abnormalities differ in their penetrance; environmental effects have not been taken into consideration; and many diseases have complex etiologies that depend on variations in a number of different genes • There are very few diseases that are caused by a single gene mutation 1 Start with Phenomenology Then, where possible, work our way to explanatory mechanisms 2 The mother and daughter are heterozygous for the same dominant mutant allele of the pax-3 gene This mutant allele shows variable expressivity Expressivity: the degree to which a particular genotype is expressed in the phenotype Variable expressivity: a variable phenotype is seen among individuals of the same genotype (with respect to the trait in question) Genes that sense gravity in plants may play a role in Waardenburg syndome in humans: http://fire.biol.wwu.edu/trent/trent/BizarreModels.pdf 3 ÒTo assess expressivity, you must examine a two or more individuals who are the same genotype with respect to the specific gene under examination 4 An “extreme”form of variable expressivity: Penetrance: the proportion of individuals with a specific genotype who manifest that genotype at the phenotype level Incomplete penetrance: not every individual of a given genotype shows the expected phenotype; that is, the phenotypic effects of the allele are not always seen in the individual 5 Attention to detail. Is there anything unusual in this photo? 6 http://fire.biol.wwu.edu/trent/trent/JakeMooreRetinoblastoma.pdf Meet Jake Moore. In Nov (2005) a family friend noticed an odd white reflection in his right eye. His left eye shows the typical redeye effect seen when the retina reflects light from a camera flash 7 Jake was subsequently diagnosed with retinoblastoma, a pediatric eye cancer that affects 1 in 20,000 children. Jake’s right eye already had two advanced tumors Retinoblastoma in humans • Tumor of the retina that forms in retinoblasts (retinal stem cells) • Can be inherited via an autosomal dominant predisposition • Rb-= mutant Rb+= normal • Rb+ Rb+ eye cancers rare (normal) • Rb+ Rb- 90% of hets get eye cancers (# tumors varies) • Rb+ Rb- 10% of hets never get eye cancers • mechanism of incomplete penetrance known (see below) • Variable # tumors in affected individuals an example of variation in expressivity Fragile X Syndrome Phenomenology 8 Explore Genetics Home Reference http://ghr.nlm.nih.gov/gene/FMR1 Fragile X syndrome is one of the most common forms of inherited mental retardation. The syndrome occurs in approximately 1 in 3600 males and 1 in 4000 to 6000 females" (fragilex.org). Fragile X results in apparently normal neurological development, with the effects becoming apparent during early learning (age 3-5). This disease is one of several CAG expansion diseases Human Molecular Genetics, 1997, Vol. 6, No. 11 1791–1801 One son (II-4) inherited a normal chromosome and the other five inherited the fragile-X chromosome 9 What mechanisms could explain incomplete penetrance and variable expressivity? 10 How can two individuals with the same genotype (for a particular trait) show different phenotypes? A norm of reaction describes the pattern of phenotypic expression of a single genotype across a range of environments 11 Mechanisms underlying incomplete penetrance and variable expressivity (i) variations in the environment to which the individuals are exposed (ii) inherent element of randomness (noise) in molecular, biochemical and developmental processes such as: • random variation in the growth and division or differentiation of cells during development • random variation in gene expression – perhaps related to epigenetic events such as DNA methylation and/or histone modification • effects of random events -- somatic mutations that produce cancer (iii) variations in the genotype at other loci -- that is, variation in genetic background (such as at modifier or suppressor loci) 12 Required Reading: The Interpretation of Genes Natural History 10/02 pg. 52-58 http://fire.biol.wwu.edu/trent/trent/interpretationofgenes.pdf The theme of this article: The “expression of a genome is best understood as a dialogue with an organism’s environment. SEE examples on the following pages: we will not discuss all of them in class. If you find a interesting example of a gene X environment interaction in the specification of a welldefined phenotype, please bring it to CT’s attention. 13 Other dramatic examples of the effects of environment on phenotype The water flea Daphnia lumholtzi usually reproduces parthenogenetically: • diploid females produce diploid daughters without interference by the rare and much smaller males. • the progeny of this form of parthenogenesis are genetic clones of the female (in contrast to what we saw with the Komodo Dragon) The individuals shown are genetic clones: • the animal on the left was exposed to chemical cues from predaceous fish • the animal on the right was a control • The sharp helmet and extended tail spine of the flea on the left protects it from predators Science 294: 321 Oct 12, 2001 14 from Natural History article referenced above These sisters are 75% identical in genotype Whether they become soldiers, workers or queens depends on a set of environmental cues -- food, temperature and light 15 16 PKU= recessive, loss-of-function mutation in enyzme that catalyzes step A in the diagram on the next page 1/12,000 (Caucasian births) affected with PKU (autosomal recessive ) Info about PKU http://www.ygyh.org/ PAH = phenyl alanine hydroxylase 17 PKU= recessive, loss-of-function mutation in enzyme (PAH) that catalyzes step A See also text reading assignments 18 aspartame: nutrasweet Asp-Phe dipeptide 19 What does the term stochastic mean? 20 Òinvolving a random variable Òhaving an inherent element of randomness or chance A model of phenotypic determination that shows how genes, environment and developmental noise interact to produce a phenotype 21 Mechanisms underlying incomplete penetrance and variable expressivity (i) variations in the environment to which the individuals are exposed (ii) inherent element of randomness (noise) in molecular, biochemical and developmental processes such as: • random variation in the growth, division, migration or differentiation of cells during development • random variation in gene expression – perhaps related to epigenetic events such as DNA methylation and/or histone modification • effects of random events such as somatic mutations that produce cancer (iii) variations in the genotype at other loci -- that is, variation in genetic background (such as at modifier or suppressor loci) 22 Role of spontaneous somatic mutation in retinoblastoma, a childhood disease marked by retinal tumors Inherited retinoblastoma: autosomal dominant predisposition to the development of retinoblastomas but the mutant allele is recessive at the cellular level HUH? 23 Tumors only arise from retinal cells that carry two mutant Rb− alleles. (a) In hereditary retinoblastoma, a child receives a normal Rb+ allele from one parent and a mutant Rb− allele from the other parent. A single mutagenic event in a heterozygous somatic retinal cell that inactivates the normal allele will result in a cell homozygous for two mutant Rb− alleles. (b) In sporadic retinoblastoma, a child receives two normal Rb+ alleles. Two separate somatic mutations, inactivating both alleles in a particular cell, are required to produce a homozygous Rb−/Rb− retinal cell. (about 1 in 30,000 Rb+/Rb+ individuals will develop retinoblastoma) 24 the stochastic nature of mutational events explains the incomplete penetrance and variable expressivity what are the elements of randomness ? if an Rb à rb mutation occurs in a retinoblast (accounts for incomplete penetrance) when and where (which eye and which retinoblast) accounts for at least some aspects of variable expressivity 25 Frequency of retinoblastoma worldwide: 1/30,000 - 1/20,000 children 5-10% of cases are inherited (pre-existing germline mutation) 20-30% of cases result from a new germline mutation in one parent 60-70% are sporadic somatic mutations CLICK HERE FOR MORE INTERESTING INFO ON RETINOBLASTOMA: http://fire.biol.wwu.edu/trent/trent/RBinfo.pdf 26 NOTE: most examples of incomplete penetrance or variable expressivity are NOT explained by the requirement of a second mutation to reveal the mutant phenotype Genetic background (to be explored in subsequent lectures), the environment, epigenetic effects and other kinds of stochastic developmental events (noise) will likely underlie the disconnect between genotype and phenotype 27 Epigenetic effects or changes– heritable changes in gene expression that do not involve changes in the DNA sequence Epigenetic mechanisms are affected by several factors and processes including development in utero and in childhood, environmental chemicals, drugs and pharmaceuticals, aging, and diet 28 Genes as a Mirror of Your Life rather than your life as a mirror of your genes https://commonfund.nih.gov/EPIGENOMICS/figure.aspx 29 30 Figure 1 Mechanisms involved in chromatin modifications Five broad and interrelated mechanisms are known to affect chromatin structure: DNA methylation, histone modification, insertion of histone variants, remodeling complexes, and noncoding RNAs. All five have been shown to be essential contributors to the development and cell fate determination of tissues including in the nervous system, while histone modifications and DNA methylation have so far been more extensively investigated in the context of adult brain function. Nature. 2010 June 10; 465(7299): 728–735. 31 32 Fragile X syndrome: variable expressivity and incomplete penetrance A loss of function of the FMR-1 gene results in severe learning problems, intellectual disability (retardation) and, for some, autism or autism-like behaviors 33 Understanding Fragile X FMR1 = Fragile X Mental Retardation 1 In family that we are considering, mom is heterozygous for a normal allele with 29 repeats and a “premutation” allele with 65 repeats 34 29/65 ~66 & 300 ~300 45% IQ 72 ~130-200 ~100-270 ~170 ~170 3% 3% 120 92 ~ 29 0% 122 I-2 has a normal allele with ~ 29 CGG repeats and an allele with an expanded repeat in the pre-mutation range (~ 65 repeats). ~130-670 100% 58 ~170-200 ~200 & 530 45% 62 CmepG (methylated) alleles shown in bold and larger font; unmethylated copies in smaller font NOTE: all offspring inheriting the permutation (fragile X allele with ~65 repeats) are somatic mosaics – different cells have alleles with different numbers of repeats and levels of DNA methylation. % methylation at a specific site in the repeat area indicated by degree of shading and % 35 Somatic mosaicism is the presence of genetically distinct populations of somatic cells in a given organism. It is frequently masked, but it can also result in major phenotypic changes Mosaicism can be caused by • mutations • epigenetic alterations of DNA • chromosomal abnormalities • spontaneous reversion of inherited mutations Nature Reviews Genetics 3, 748-758 (October 2002) | doi:10.1038/nrg906 36 DNA methylation-induced silencing of FMR-1 transcription results in a loss of gene function à severe effects on nervous system http://ghr.nlm.nih.gov/gene/FMR1 37