Beyond Mendel’s Laws of Inheritance 2006-2007

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

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

Incomplete dominance P F1 100% 1:2:1 F2 X true-breeding red flowers white flowers 100% 100% pink flowers F1 generation (hybrids) self-pollinate 25% white F2 generation 25% red 1:2:1 50% pink

Incomplete dominance CRCW x CRCW CRCR CR CW CRCW CRCR CRCW CR CW CRCW % genotype % phenotype CRCR 25% 25% CR CW male / sperm 50% 50% CRCW CRCR CRCW CR CW female / eggs CRCW CWCW CRCW CWCW 25% 25% 1:2:1 1:2:1

Incomplete Dominance Example Morning glories show incomplete dominance. Purple flowers come from crossing blue-flowered and red-flowered plants. How can I get the most purple-flowered plants? 1st – Find letters! 2nd – Work backwards!

Example Cont’d CB CB CR CRCB CRCB CR CRCB CRCB Crossing a homozygous red-flowered plant with a homomzygous blue-flowered plant would yield the most purple flowered plants. CR CRCB CRCB

Codominance - Blood Types 2 alleles affect the phenotype equally & separately not blended phenotype example: ABO blood groups 3 alleles (multipl 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 markers on the surface of red blood cells

Multiple Alleles - Blood Types Multiple Alleles – 3 or more kinds of alleles per gene spot. Blood types are codominant AND have multiple alleles B = gene for Blood type. It has three alleles: A, B, and O H = gene for Height. It has two allele forms, T and t H H B B

Genetics of Blood type A IA IA or IA i B IB IB or IB i AB IA IB O i i pheno-type genotype antigen on RBC antibodies in blood donation status A IA IA or IA i type A antigens on surface of RBC anti-B antibodies __ B IB IB or IB i type B antigens on surface of RBC anti-A antibodies AB IA IB both type A & type B antigens on surface of RBC no antibodies universal recipient O i i no antigens on surface of RBC anti-A & anti-B antibodies universal donor

Blood compatibility 1901 | 1930 Matching compatible blood groups critical for blood transfusions A person produces antibodies against antigens in foreign blood wrong blood type donor’s blood has A or B antigen that is foreign to recipient antibodies in recipient’s blood bind to foreign molecules cause donated blood cells to clump together can kill the recipient Karl Landsteiner (1868-1943)

Blood donation clotting clotting clotting clotting clotting clotting

Blood Type Example 1: Mom is Type A. Dad is Type O. What are the blood type possibilities for the kids?

Blood Type Example 1 Cont’d Mom’s possible genotypes: IAIA or IAi Dad’s genotype: ii i IA IAi ii i IA IAi

Blood Type Example 2 Mom is Type A and the child is Type B. She says Burt is the father. Burt has Type O blood. Is he the baby’s father?

Blood Type Example 2 Cont’d Mom is IAIA or IAi Burt is ii Baby is IBIB or IBi NOT possible, as the baby could not have gotten an IB allele from either of these two people. Blood typing: Determining if a child is NOT the offspring of two parents.

Codominance - Sickle Cell Sickle cell anemia is another example of codominance in humans. No sickle cell anemia (homozygous normal) = HNHN All blood cells are normal in shape Sickle cell anemia (homozygous abnormal) = HSHS Blood cells are sickle shaped Heterozygous individuals (HNHS) can still experience health problems, as BOTH the normal and abnormal alleles are codominant.

Sickle-Cell Anemia Cont. The life space of the sickle-shaped blood cells are shorter than that of normal blood cells. A lower number of red blood cells causes the patient to also suffer from Anemia.

A note on dominance Because an allele is dominant does not mean… it is better, or it is more common Polydactyly dominant allele

Polydactyly recessive allele far more common than dominant individuals are born with extra fingers or toes the allele for >5 fingers/toes is DOMINANT & the allele for 5 digits is recessive recessive allele far more common than dominant  only 1 individual out of 500 has more than 5 fingers/toes  so 499 out of 500 people are homozygous recessive (aa)

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) The genes that we have covered so far affect only one phenotypic character, but most genes are pleiotropic

Acromegaly: André the Giant

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

Sex linked traits 1910 | 1933 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

Classes of chromosomes autosomal chromosomes sex chromosomes

Discovery of sex linkage true-breeding red-eye female true-breeding white-eye male X P 100% red eye offspring F1 generation (hybrids) 100% red-eye female 50% red-eye male 50% white eye male F2 generation

What’s up with Morgan’s flies? x x RR rr Rr Rr  r r R r R Rr Rr R RR Rr Doesn’t work that way! R Rr Rr r Rr rr 100% red eyes 3 red : 1 white

Genetics of Sex X Y X XX XY X XX XY In humans & other mammals, there are 2 sex chromosomes: X & Y 2 X chromosomes develop as a female: XX gene redundancy, like autosomal chromosomes an X & Y chromosome develop as a male: XY no redundancy X Y X XX XY X XX XY 50% female : 50% male

What’s up with Morgan’s flies? x x XRXR XrY XRXr XRY Xr Y XR Y  XR XR XRXr XRY XRXR XRY BINGO! XR Xr XRXr XRY XRXr XrY 100% red females 50% red males; 50% white males 100% red eyes

Genes on sex chromosomes Y chromosome few genes other than gender determinant sex-determining region master regulator for maleness turns on genes for production of male hormones many effects = pleiotropy! X chromosome other genes/traits beyond sex determination mutations: hemophilia Duchenne muscular dystrophy color-blindness Male-pattern baldness Duchenne muscular dystrophy affects one in 3,500 males born in the United States. Affected individuals rarely live past their early 20s. This disorder is due to the absence of an X-linked gene for a key muscle protein, called dystrophin. The disease is characterized by a progressive weakening of the muscles and loss of coordination.

Human X chromosome Sex-linked usually means “X-linked” Duchenne muscular dystrophy Becker muscular dystrophy Ichthyosis, X-linked Placental steroid sulfatase deficiency Kallmann syndrome Chondrodysplasia punctata, X-linked recessive Hypophosphatemia Aicardi syndrome Hypomagnesemia, X-linked Ocular albinism Retinoschisis Adrenal hypoplasia Glycerol kinase deficiency Incontinentia pigmenti Wiskott-Aldrich syndrome Menkes syndrome Charcot-Marie-Tooth neuropathy Choroideremia Cleft palate, X-linked Spastic paraplegia, X-linked, uncomplicated Deafness with stapes fixation PRPS-related gout Lowe syndrome Lesch-Nyhan syndrome HPRT-related gout 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 Androgen insensitivity Chronic granulomatous disease Retinitis pigmentosa-3 Norrie disease Retinitis pigmentosa-2 Sideroblastic anemia Aarskog-Scott syndrome PGK deficiency hemolytic anemia Anhidrotic ectodermal dysplasia Agammaglobulinemia Kennedy disease Pelizaeus-Merzbacher disease Alport syndrome Fabry disease Albinism-deafness syndrome Fragile-X syndrome Immunodeficiency, X-linked, with hyper IgM Lymphoproliferative syndrome Ornithine transcarbamylase deficiency Human X chromosome Sex-linked usually means “X-linked” more than 60 diseases traced to genes on X chromosome

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

X-inactivation & tortoise shell cat 2 different cell lines in cat

Map of Human Y chromosome? < 30 genes on Y chromosome Sex-determining Region Y (SRY) Channel 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) linked Spitting (P2E) Inability to express affection over phone (ME-2) Selective hearing loss (HUH) Total lack of recall for dates (OOPS)

Sex-linked traits summary follow the X chromosomes males get their X from their mother trait is never passed from father to son Y-linked very few genes / traits trait is only passed from father to son females cannot inherit trait

Hemophilia is a sex-linked recessive trait defined by the absence of one or more clotting factors. These proteins normally slow and then stop bleeding. Individuals with hemophilia have prolonged bleeding because a firm clot forms slowly. Bleeding in muscles and joints can be painful and lead to serious damage. Individuals can be treated with intravenous injections of the missing protein.

Sex Linked Example: Hemophilia Hemophilia is recessive to normal blood clotting and sex-linked. Letters? Normal = N Hemophilia = n What are the chances of having a child with hemophilia if Dad is normal and mom is a carrier? Carriers are individuals that carry an allele for the disease, but usually do not have the disease themselves

Hemophilia XNXn XNY Hh x HH XN XNXn XN Y Xn XHXH XNXN XNY XHY XN Xn XN Hemophilia is sex-linked recessive Hemophilia XNXn XNY Hh x HH XN XNXn XN Y male / sperm Xn XHXH XNXN XNY XHY XN Xn female / eggs XN XNY XHXh XNXn XhY XnY Y carrier disease

is sex-linked & recessive Male pattern baldness Sex influenced trait autosomal trait influenced by sex hormones age effect as well = onset after 30 years old Letters? Normal = N Bald = n Male Pattern baldness is sex-linked & recessive

Sex Linked Example: Baldness Regular Hair is normal and sex-linked. Cross carrier (heterozygous) female with normal male. Letters? Normal = N Bald = n Parents? XNXn x XNY Remember, for baldness the Y chromosome NEVER has a sex-linked gene!

Sex Linked Example Cont’d Cross: XNXn x XNY Genotypes: 1 XNXN, 1 XNXn, 1 XNY, 1 XnY Phenotypes: 1 Female, Normal 1 Female carrier 1 Male, Normal 1 Male, bald Males only need one recessive to have the condition! XN Y XN XNXN XNY XNXn XnY Xn