Mendelian Genetics Exceptions Human Genetics Mendelian Genetics Exceptions 1

Gene (allele) interactions Dominance Recessive Codominance Incomplete dominance Epistasis Pleiotropy Linkage Penetrance Expressivity Environmental factors

Exceptions to Mendel’s Laws Mendel chose traits in peas that showed two distinct forms. Not all genes exhibit such simple inheritance. Alleles interact Genes interact Non-nuclear genes exist Segregation of genes on same chromosome

Lethal Allele Combinations Homozygous recessive lethal alleles eliminate a progeny class. Sometimes this is hard to see in a family- it may result in reduced fertility.

Genetic Disease is an Important Component of Childhood Mortality These lethal genetic combinations could be homozygous recessive, heterozygous dominant, homozygous dominant, chromosomal deletions/duplications or multiple genes interacting Many Human Geneticists are pediatricians Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins

Age at Expression of Genetic Disease Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins

Lethals can be considered Semidominant The phenotype of the homozygote is more extreme than the phenotype of the heterozygote. The normal allele of this gene is expressed in the embryo. Carriers can have a phenotype but the homozygotes die as early embryos. Allele is maintained by crosses of heterozygotes and new mutations.

Mexican Hairless Dogs

Multiple Alleles A gene can have more than two alleles, but a diploid individual only has one or two of them. Different allele combinations can produce different phenotypes and different severities of symptoms.

Multiple Alleles An individual has two alleles, but a population can have many alleles within the individual members. Genes can mutate in many ways at any nucleotide in their DNA sequence. Eye Color and Hair color are examples of multiple alleles

Multiple Alleles in Rabbit Coat Color Grey CC or Ccch or Cch or Cc Chinchilla cchcch Himalayan chc or chch Light gray cchch or cchc Albino cc

Codominant Alleles

Epistasis The masking of the action of an allele of one gene by the allelic combinations of another gene. The interaction of nonallelic genes in the formation of the phenotype. Common indicator of epistasis: the F2 generation of a dihybrid cross will be a variation of the 9:3:3:1 phenotypic ratio Example: Flower Color

Epistasis in flower color

Epistasis in flower color

Bombay Phenotype Epistasis H gene is epistatic to the ABO gene. H protein attaches the A or B protein to the cell surface. hh genotype = no H protein. All ABO genotypes appear as type O.

H structure: Mucopolysaccharide found on the surface of RBCs

How are Autosomal Dominant Diseases maintained in populations? Since every mutant allele for an autosomal dominant disease is expressed, and by definition a disease is a deleterious phenotype, shouldn't autosomal diseases be eliminated by natural selection against deleterious phenotypes? Four phenomena maintain these deleterious alleles in the population: Variable Expressivity Late Onset High Recurrent Mutation Rate Incomplete Penetrance

Incomplete Dominance Incomplete dominance may lead to a distortion of the apparent ratios or to the creation of unexpected classes of offspring. Familial Hypercholesterolemia (FH). Here there are three phenotypes: +/+ = normal +/- = death as young adult -/- = death in childhood. The gene codes for the liver receptor for cholesterol. The number of receptors is directly related to the number of active genes. If the number of receptors is lowered the level of cholesterol in the blood is elevated and coronary artery disease risk is higher.

Familial Hypercholesterolemia Top number is pedigree number, bottom is age the trait is diagnosed. Can we say if person II-5 might be a carrier, since they are still young? Persons III-6, III-7 and III-8 show symptoms early WV study Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins

Penetrance Probability that a disease phenotype will appear when a disease-related genotype is present. Both genetic and environmental factors can affect penetrance.  DD or Dd 80% polydactyly DD or Dd 20% no polydactyly Incomplete penetrance occurs when the disease phenotype is not always observed among individuals carrying the disease-associated genotype.

Incomplete or Variable Penetrance Incomplete penetrance is not the same as variable expressivity. In diseases with variable expressivity, the patient always expresses some of the symptoms of the disease and varies from very mildly affected to very severely affected. In autosomal dominant diseases with incomplete penetrance, the person either expresses the disease phenotype or he/she doesn't. Incomplete penetrance and variable expressivity are phenomena associated only with dominant inheritance, never with recessive inheritance.

Incomplete Penetrance The disease is passed from the father (II-3) to the son (III-5), this never happens with X-linked traits. The disease occurs in three consecutive generations, this never happens with recessive traits. Males and females are affected, with roughly the same probability. However, II-1 does not express the disease. He must have inherited the mutant allele because he passed it on to two children, III-1 and III-3. II-1 is a classical example of incomplete penetrance, he has the allele for the disease but he does not express it.

Von Hippel-Lindau (VHL) disease OMIM 193300 Dominantly inherited familial cancer syndrome predisposing to various benign or malignant tumors: central nervous system (CNS) ocular hemangioblastomas (tumor composed of hemangioblasts, a type of stem cell that normally give rise to blood vessels or blood cells). renal cell carcinoma (RCC) and/or renal cysts, pancreatic tumors and cysts. The birth incidence is estimated to be 1 in 36,000 to 1 in 53,000. Retinal Hemangioblastoma in von Hippel-Lindau Disease: A Clinical and Molecular Study ()Hélène Dollfus et al. Investigative Ophthalmology and Visual Science. 2002;43:3067-3074

Age at Appearance of first Hemangioblastoma Retinal Hemangioblastoma in von Hippel-Lindau Disease: A Clinical and Molecular Study ()Hélène Dollfus et al. Investigative Ophthalmology and Visual Science. 2002;43:3067-3074

Several mutations involved, leading to differences in activity of the mutant protein, which is a tumor suppressor. Retinal Hemangioblastoma in von Hippel-Lindau Disease: A Clinical and Molecular Study ()Hélène Dollfus et al. Investigative Ophthalmology and Visual Science. 2002;43:3067-3074

Factors affecting gene expression Many genes give consistent and regular patterns of expression. Some genotypes – the phenotypes may vary. gene – gene interaction gene- environment interaction Examples: temperature, age

Various factors, both genetic and environmental can affect the colour of the Siamese cat. As the points and body colour are temperature sensitive, an important factor in the depth of pigmentation is the amount of heat loss from the skin. Colour is affected by climatic conditions, for instance in Australia the Northern Territory's hot climate has a dramatic effect on Seal Point Siamese, whose points become brindled, with cream and seal hairs intermingling. In contrast , studs and other cats kept in an outdoor cattery in Tasmania's winter cold, have dense seal points and are darker in the body. Theoretically, if we keep our Siamese warm, especially Seal Points, the lighter their body colour should be. But not too warm, as an elevation in temperature can cause brindling, or loss of pigmentation in the points; often seen after the cat has been ill. Siamese grow out darker on the body after surgery, and white hairs can appear on the points when the follicles are damaged. Age is another factor, and the sites of intense pigmentation appear on the shoulders and hips where the skin is closest to the underlying bone structure. The lighter the colour the more sensitive to heat - Chocolate is more sensitive to heat than Seal (Black) - hence the difficulty in breeding a Chocolate Point with perfectly even points. That temperature alone effects colour is an over-simplification as there are many other genetic factors, including modifiers and polygenes. When visiting theLindisfarne Cattery in Auckland, New Zealand in 1964, I saw the UK import Spotlight Pride, who at 15 years old had a clear cream coat and dense seal points. In stark contrast, their other male Morris Maestro, also IMP UK, was extremely dark all over - almost a self-seal. Both studs were housed under identical conditions, so their disparity of colour must have been genetic. Various factors, both genetic and environmental can affect the colour of the Siamese cat. As the points and body colour are temperature sensitive, an important factor in the depth of pigmentation is the amount of heat loss from the skin. Colour is affected by climatic conditions, for instance in Australia the Northern Territory's hot climate has a dramatic effect on Seal Point Siamese, whose points become brindled, with cream and seal hairs intermingling. In contrast , studs and other cats kept in an outdoor cattery in Tasmania's winter cold, have dense seal points and are darker in the body. That temperature alone effects colour is an over-simplification as there are many other genetic factors, including modifiers and polygenes. When visiting theLindisfarne Cattery in Auckland, New Zealand in 1964, I saw the UK import Spotlight Pride, who at 15 years old had a clear cream coat and dense seal points. In stark contrast, their other male Morris Maestro, also IMP UK, was extremely dark all over - almost a self-seal. Both studs were housed under identical conditions, so their disparity of colour must have been genetic.

How might this Nerve Disorder with Leg Weakness be inherited? Don is affected and Tom Jr. is concerned that he not pass the disorder on to his children with Alice. What can we conclude about Tom Sr, who died in a car wreck? Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins

Autosomal Dominant with Variable Age of Onset 50% for Tom 25% chance for child Don is ill and Tom Jr. is concerned that he not pass the disease on to his children with Alice. What about Tom Sr, who died in a car wreck? Tom Sr. had the trait and passed it to Don Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins

Pleiotropy Examples: Marfan Syndrome; Porphyria The appearance of several apparently unrelated phenotypic effects caused by a single gene refers to a Mendelian disorder with several symptoms Different subset of symptoms in different individuals. Usually means that a genes is involved in multiple processes Examples: Marfan Syndrome; Porphyria  

Porphyria Autosomal dominant Many symptoms due to variety of problems with porphyrin accumulation Photo © North Wind Picture Archives

Marfan Syndrome Inheritance - autosomal dominant   Inheritance - autosomal dominant Phenotype - tall and thin, with long extremities, deficiencies in the skeletal system, eyes and cardiovascular system. Defect - defective gene on chromosome 15 Affected gene produces abnormal fibrillin End result - abnormal connective tissue Major problem - aorta rupture 1 in 10000 occurrence Both male and females afflicted 25% of cases occur in families with no previous history Reason - gene undergoes a high mutation rate

Normal Marfan Syndrome

Marfan’s Syndrome Pedigree

The debate over Lincoln In the early 1960s, Dr. A.M.Gordon addressed the Kentucky State Medical Association suggesting that President Abraham Lincoln had Marfan syndrome. The diagnosis was based written physical descriptions of Lincoln: He was much taller than most men of his day, Long limbs An abnormally-shaped chest Loose (lax) joints Since then, other physicians have disputed a diagnosis of Marfan syndrome for Lincoln.

Genetic heterogeneity Different genes can produce identical phenotypes. Individuals with identical phenotypes may reflect different genetic causes. Deafness Albinism Cleft palate Poor blood clotting

Autosomal Deafness

Phenocopy A trait caused by the environment that appears inherited. Exposure to teratogens Thalidomide causes limb defects akin to rare inherited phocomelia. Infection Rubella in pregnant mothers causes deafness mimicking inherited forms of deafness.

Imprinting Epigenetics has become a huge area of active research Nova- The Ghost in your genes.