Lecture 1: Basic Concepts and Terminology PDF

Lecture 1 Basic concepts and terminology TERMS & DEFINITIONS EUKARYOTE: “true nucleus” DIPLOID: two copies of each gene (maternal & paternal) HAPLOID: one copy of each gene (gamete) GENE: a fragment of DNA encoding RNA TERMS & DEFINITIONS ALLELES: alt...

Lecture 1 Basic concepts and terminology TERMS & DEFINITIONS EUKARYOTE: “true nucleus” DIPLOID: two copies of each gene (maternal & paternal) HAPLOID: one copy of each gene (gamete) GENE: a fragment of DNA encoding RNA TERMS & DEFINITIONS ALLELES: alternative forms of same gene (b-globin & sickle-cell b-globin) wild-type & mutant allele HOMOLOGUES: copies related by descent; (HOMOLOGOUS) same gene in different species (eg. chimpanzee and human b-globin genes) HOMOLOGOUS ORTHOLOGOUS The clusters of β-like globin genes are homologous Cold Spring Harb Perspect Med. 2012 Dec; 2(12):  The β-like globin genes in each cluster are paralogous Cold Spring Harb Perspect Med. 2012 Dec; 2(12): High similarity might also occur  by chance (i.e, short sequences)  by convergent evolution Such sequences are similar (analogous) but not homologous. GENETIC NOMENCLATURE b gene for b –globin b + wild-type allele b +/b + HOMOZYGOTE diploid, same alleles GENETIC NOMENCLATURE GENOTYPE specific allele composition PHENOTYPE ‘form that is seen’ HAPLOTYPE DNA variations (polymorphisms), that tend to be inherited together. GENETIC NOMENCLATURE b SC sickle-cell allele b SC /b SC homozygote sickle-cell b +/b SC HETEROZYGOTE diploid with different alleles  βSC is the result of the substitution of Val for Glu at the 7th amino acid position of the β-chain. 10 20 30 40 50 MVHLTPEEKS AVTALWGKVN VDEVGGEALG RLLVVYPWTQ RFFESFGDLS 60 70 80 90 100 TPDAVMGNPK VKAHGKKVLG AFSDGLAHLD NLKGTFATLS ELHCDKLHVD 110 120 130 140 PENFRLLGNV LVCVLAHHFG KEFTPPVQAA YQKVVAGVAN ALAHKYH People who are heterozygous b +/b SC have sickle cell trait and are largely asymptomatic, whereas b SC/ b SC homozygous have sickle cell anaemia. Phenotype of the b +/b SC heterozygote? What do we learn from it? Phenotype of the b +/b SC heterozygote?  PHENOTYPE OF HETEROZYGOTE defines the relationships between alleles  In normal oxygen conditions b + is DOMINANT over b SC b SC is RECESSIVE to b +  In limited oxygen we see the “sickle cell” trait b SC is not fully RECESSIVE to b + INCOMPLETE/PARTIAL DOMINANCE of b + over b SC Incomplete dominance is when the heterozygous has a phenotype that is in between the phenotypes of the two homozygous. Historically, sickle cell anaemia caused early mortality  Natural selection should have removed the allele from populations  Why is the b sc allele still maintained in human populations? Malaria (left) versus sickle-cell trait (right) distributions Allison AC., Bioch. & Mol. Biol. Edu., Vol. 30, No. 5, pp. 279 –287, 2002 Sickle-cell trait protects against malaria Allison AC., Br Med J., 1954 Feb 6, 1(4857):290-4. doi: 10.1136/bmj.1.4857.290. Mechanism of protection Luzzatto L., Mediterr J Hematol Infect Dis., 2012 4(1): e2012065  Heterozygote advantage, or heterotic balancing selection the heterozygous [for a particular gene] has a greater fitness than either of the two homozygous More generally Balancing Selection is a processes by which selection maintains multiple alleles in the gene pool of a population at frequencies higher than what can be predicted by mutation alone. [Examples are: Clinal variation, frequency-dependent selection, developmental-related fitness] Incomplete dominance must not be confused with codominance which, is when both alleles of the heterozygous contribute equally to the phenotype.  ABO BLOOD GROUP SYSTEM 4 phenotypes: A, B, AB, O 2 antigens A and B One gene: I. Three alleles: IA, IB and iO (recessive)  ABO BLOOD GROUP SYSTEM Phenotyp Antigen Serum Genotyp e on rbc antibody e A A anti-B IA/IA or IA/iO B B anti-A IB/ IB or IB/iO AB A&B none IA/IB O none anti-A & iO/iO anti-B  Gene I encodes for a glycosyltransferase, an enzyme that adds a sugar group Enzyme from allele IA adds N-acetylgalactosamine Enzyme from allele IB adds galactose Enzyme from allele iO is inactive Alleles IA and IB differ by 4 base pairs (substitutions) Allele iO has a frameshift mutation DOMINANT MUTATIONS  Achondroplasia  Achondroplasia is a disorder of bone growth that causes the most common type of dwarfism. DOMINANT MUTATIONS  Achondroplasia symptoms may include: Bowed legs Large head-to-body size difference Prominent forehead Shortened arms and legs Short stature Spinal stenosis Spine curvatures called kyphosis and lordosis DOMINANT MUTATIONS  Achondroplasia may be inherited as an autosomal dominant trait: If one parent has the defective gene, the child will have 50% chance of inheriting the disorder. If both parents have the condition, the infant's chances of being affected increase to 75%. DOMINANT MUTATIONS  Achondroplasia, most cases appear as spontaneous mutations. This means that two parents without achondroplasia may give birth to a baby with the condition. The prevalence is approximately 1 in 25,000 births DOMINANT MUTATIONS  Achondroplasia causes  A mutation in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene, which causes an abnormality of cartilage formation.  FGFR3 has a negative regulatory effect on bone growth.  In achondroplasia, the mutated form of the receptor is constitutively active and this leads to severely shortened bones. DOMINANT MUTATIONS Huntington’s disease (chorea)  Late onset (35-50), neurodegenerative, affects 1/ 10,000  Death within 15-20 yrs of onset  Gene identified (1993), function not entirely known  Gene has CAG repeats (polyglutamine) Normal gene, 6–35 repeats Disease gene, 36–121 repeats with the number of repeats being inversely correlated with the age of onset of the disease  DOMINANT MUTATIONS Possible molecular explanations  Regulated protein; normally expressed at a critical moment during development is expressed constitutively (constantly) in the mutant  Novel function of the mutant protein; for instance an enzyme making a different product GAIN OF FUNCTION  DOMINANT MUTATIONS Possible molecular explanations  Structural protein; may be insufficient if only one gene copy is active  Multimeric protein; mutant polypeptide may ‘poison’ the assembly LOSS OF FUNCTION Epistasis  Gene interactions that affect the phenotype Whenever two or more loci interact to create new phenotypes Whenever an allele at one locus masks the effects of alleles at one or more other loci Whenever an allele at one locus modifies the effects of alleles at one or more other loci Epistasis Epistasis  Epistasis Purple is epistatic to Pattern Epistasis Epistasis Epistasis Purple is epistatic to Pattern. Is Purple epistatic to Transporter ? Is Transporter epistatic to Purple ? Is Transporter epistatic to Pattern ? Penetrance and Expressivity Identical genes produce different expression patterns This can be explained by the fact that the expression of individual genes is influenced by other genes in the genome of that particular individual, i.e. the genetic background, and by its interactions with the environment.  Incomplete Penetrance  When the presence of a particular allele results in a defined phenotype in some but not all individuals.  If, for instance, only 85% of people having the same genotype show a phenotype the penetrance if 85%  Incomplete Penetrance The majority of people with Osteogenesis Imperfecta (OI) have a dominant mutation in one of the two genes that produce type 1 collagen, COL1A1 or COL1A2. However, some people can carry a mutation but have no symptoms.  Expressivity Polydactyly in cats. The responsible allele always causes extra toes on the paw, but the number of extra toes varies widely from cat to cat Individuals with the same genotype can show different degrees of the same phenotype.