Beyond Mendel’s Laws of Inheritance

1. Beyond Mendel’s Laws of Inheritance

2. Extending Mendelian genetics • Mendel worked with a simple system • peas are genetically simple • most traits are controlled by a single gene • each gene has only 2 alleles, 1 of which is completely dominant to the other • The relationship between genotype & phenotype is rarely that simple

3. Alleles • For every gene, there are many different alleles • versions of the same gene that differ in their DNA base sequence • Some alleles differ in the protein product of the gene • Your combination of alleles is unique, and makes you you • Alleles are generated by mutations • Variation preceded adaptation

4. Dominant vs. Recessive • Common misconception: Recessive allele is not expressed. This is not always true! • Tay sachs: lipids can’t be metabolized • Organismal recessive, biochemically incomplete dominant, molecularly codominant • Half of wild type is enough

5. Lethal Alleles • Essential genes are those that are absolutely required for survival • The absence of their protein product leads to a lethal phenotype • It is estimated that about 1/3 of all genes are essential for survival • A lethal allele is one that has the potential to cause the death of an organism • These alleles are typically the result of mutations in essential genes

6. Lethal Alleles • Many lethal alleles prevent cell division • Some lethal alleles exert their effect later in life • Huntington disease • Characterized by progressive degeneration of the nervous system, dementia and early death • The age of onset of the disease is usually between 30 to 50 • A lethal allele may produce ratios that seemingly deviate from Mendelian ratios • Another example is the “creeper” allele in chicken

7. Creeper X Normal 1 creeper : 1 normal 1 normal : 2 creeper Creeper X Creeper Phenotypic Ratios Associated with Lethal Alleles Creeper is lethal in the homozygous state Creeper is a dominant allele

8. Incomplete dominance • Heterozygote shows an intermediate, blended phenotype • example: • RR = red flowers • rr = white flowers • Rr = pink flowers • make 50% less color RR Rr rr

9. 1:2:1 phenotypic ratio NOT the 3:1 ratio observed in simple Mendelian inheritance In this case, 50% of the CR protein is not sufficient to produce the red phenotype Figure 4.2

10. Multiple Alleles • The term multiple alleles is used to describe situations when three or more different alleles of a gene exist • Examples: • ABO blood • Coat color in many species • Eye color in Drosophila • Every gene? http://ghr.nlm.nih.gov/BrowseGenes, Click on OMIM and the allelic variants table.

11. Multiple Alleles • coat color in rabbits • C (full coat color) • cch (chinchilla pattern of coat color) • Partial defect in pigmentation • ch (himalayan pattern of coat color) • Pigmentation in only certain parts of the body • c (albino) • Lack of pigmentation

13. Co-dominance • 2 alleles affect the phenotype equally & separately • not blended phenotype • example: ABO blood groups • 3 alleles • IA, IB, i • IA & IB alleles are co-dominant to each other • both antigens are produced • both IA & IB are dominant to i allele • produces glycoprotein antigen markers on the surface of red blood cells

14. (a) The three alleles for the ABO blood groups and their carbohydrates Figure 14.11 Allele IA IB i none Carbohydrate B A (b) Blood group genotypes and phenotypes Genotype ii IAIA or IAi IBIB or IBi IAIB Red blood cellappearance Phenotype(blood group) A AB O B

15. Pleiotropy • Most genes are pleiotropic • one gene affects more than one phenotypic character • wide-ranging effects due to a single gene • dwarfism (achondroplasia) • gigantism (acromegaly)

16. Epistasis • One gene completely masks another gene • coat color in mice = 2 separate genes • C,c: pigment (C) or no pigment (c) • B,b: more pigment (black=B) or less (brown=b) • cc = albino, no matter B allele • 9:3:3:1 becomes 9:3:4 How would you know thatdifference wasn’t random chance? Chi-square test!

17. Polygenic inheritance • Some phenotypes determined by additive effects of 2 or more genes on a single character • human traits • skin color • height • weight • eye color • intelligence • behaviors

18. Eye Color in Humans • Controlled by at least 8 genes • Each gene has multiple alleles

19. Sex linked traits • Genes are on sex chromosomes • as opposed to autosomal chromosomes • first discovered by T.H. Morgan at Columbia U. • Drosophila breeding • good genetic subject • prolific • 2 week generations • 4 pairs of chromosomes • XX=female, XY=male

20. Genetics of Sex

21. Genes on sex chromosomes • Y chromosome • few genes other than SRY • sex-determining region • master regulator for maleness • turns on genes for production of male hormones • many effects = pleiotropy! • X chromosome • other traits beyond sex determination • mutations: • hemophilia • Duchenne muscular dystrophy • color-blindness

22. Ichthyosis, X-linked Placental steroid sulfatase deficiency Kallmann syndrome Chondrodysplasia punctata, X-linked recessive Hypophosphatemia Aicardi syndrome Hypomagnesemia, X-linked Ocular albinism Retinoschisis Duchenne muscular dystrophy Becker muscular dystrophy Chronic granulomatous disease Retinitis pigmentosa-3 Adrenal hypoplasia Glycerol kinase deficiency Norrie disease Retinitis pigmentosa-2 Ornithine transcarbamylase deficiency Incontinentia pigmenti Wiskott-Aldrich syndrome Menkes syndrome Androgen insensitivity Sideroblastic anemia Aarskog-Scott syndrome PGK deficiency hemolytic anemia Charcot-Marie-Tooth neuropathy Choroideremia Cleft palate, X-linked Spastic paraplegia, X-linked, uncomplicated Deafness with stapes fixation Anhidrotic ectodermal dysplasia Agammaglobulinemia Kennedy disease PRPS-related gout Lowe syndrome Pelizaeus-Merzbacher disease Alport syndrome Fabry disease Lesch-Nyhan syndrome HPRT-related gout Immunodeficiency, X-linked, with hyper IgM Lymphoproliferative syndrome Hunter syndrome Hemophilia B Hemophilia A G6PD deficiency: favism Drug-sensitive anemia Chronic hemolytic anemia Manic-depressive illness, X-linked Colorblindness, (several forms) Dyskeratosis congenita TKCR syndrome Adrenoleukodystrophy Adrenomyeloneuropathy Emery-Dreifuss muscular dystrophy Diabetes insipidus, renal Myotubular myopathy, X-linked Albinism-deafness syndrome Fragile-X syndrome Human X chromosome • Sex-linked • usually means“X-linked” • more than 60 diseases traced to genes on X chromosome

23. linked Map of Human Y chromosome? < 30 genes on Y chromosome Sex-determining Region Y (SRY) Channeling Flipping (FLP) Catching & Throwing (BLZ-1) Self confidence (BLZ-2)note: not linked to ability gene Devotion to sports (BUD-E) Addiction to death &destruction movies (SAW-2) Air guitar (RIF) Scratching (ITCH-E) Spitting (P2E) Inability to express affection over phone (ME-2) Selective hearing loss (HUH) Total lack of recall for dates (OOPS)

24. XHXh XH Xh X-inactivation • Female mammals inherit 2 X chromosomes • one X becomes inactivated during embryonic development • condenses into compact object = Barr body • which X becomes Barr body is random • patchwork trait = “mosaic”

25. Functions of Mitochondrion • Site of cellular respiration • Make DNA components • Detoxify ammonia in the liver • Required for heme synthesis • Cholesterol metabolism • Steroid synthesis

26. Mitochondria are Passed from Mother to Offspring • In most animals father and mother each contribute the same number of chromosomes to the zygote. • Thousands of mitochondria per egg cell, and only a few in the sperm • Once the sperm enters the egg, those sperm mitochondria are usually destroyed. • The zygote ends up filled with mitochondria from the egg, therefore the zygote inherits the maternal mitochondrial DNA.

27. Examples • myoclonic epilepsy and ragged red fiber disease (MERRF) • Leber’s hereditary optic neuropathy (LHON) • Kearns–Sayre syndrome (KSS)

28. MERRF MERRF Cells Normal Skeletal Muscle. Cross-section. http://img.medscape.com/pi/emed/ckb/neurology/1134815-1189245-1189246-1189490.jpg

29. Nature vs. nurture • Phenotype is controlled by both environment & genes Human skin color is influenced by both genetics & environmental conditions Coat color in arctic fox influenced by heat sensitive alleles Color of Hydrangea flowers is influenced by soil pH