Unit II- Mendelian Patterns of Inheritance Flashcards
Single gene, multifactorial, and chromosomal
- sometimes a particular genotype at one locus is both necessary and sufficient for the character to be expressed, given an otherwise normal genetic and environmental background- single gene
- chromosomal disorders are due to problems at chromosomal levels (deletions and translocation)
- on the other hand, many characters are dependent on a variety of genetic and environmental factors, and are said to be multifactorial
- single-gene (1.25%)
- chromosomal (0.4%)
- multifactorial (65% lifetime, 6% congenital)
Proband, First, Second, Third Degree relatives
- two individuals that are first degree relatives to each other share half their genes in common
- a quarter of their genes with a second degree relative and so on
- the sex chromosomes and mitochondria will be exceptions
Genotype
the genetic constitutionn (genome)
- the alleles present at one locus
Phenotype
- the observed biochemical, physiological, and morphological characteristics of an individual, as determined by his or her genotype
- modifier genes and the environment in which it is expressed
Genetic Heterogeneity
- allelic (genotypic) heterogeneity
- 2+ different mutant alleles at the same locus
- e.g. CF has 1900+ CFTR mutations
- locus (genotypic) heterogeneity
- mutations at 2+ loci can produce the same or similar phenotypes e.g. Retinitis Pigmentosa RP2 on Xp, RP28 on 2p and RP5 on 3q; over 30 RP loci
- e.g many genes result in mental retardation, in particular the X chromosome
Clinical or phenotypic heterogeneity
- clinical (phenotypic) heterogeneity is the association of more than one phenotype with mutations at a single locus
- examples are severity of disease (expressivity and penetrance)
- different diseases can occur due to mutations in the same gene
- several different clinical vision related diseases result of mutations in ABCR gene at 1p22.1
- multiple endocrine neoplasa, type II or Hischspring disease result from different mutations at RET gene at 10q11.2
Hirschsprung disease (HSCR)- aganglionic megacolon
absence of some ganglionic cells
Severe constipation, intestinal obstruction, massive dilation of colon
-loss of function mutations of RET gene (chromosome 10), often in males, autosomal dominant
Multiple endocrine neoplasia type II (MENII)
thryoid cancer, pheochromocytoma (benign adrenal medulla tumor) and hyperplasia (overgrowth of the parathyroid) gland
- autosomal dominant
- mutations, primarily at the cysteines at codons 609, 618, 620 of the same RET gene. Alter substate specifically
Clinical phenotype
- variable expression
- phenotype depends on the severity of the CFTR mutations
- male reproductive system lease tolerant to reduced CFTR product
Modes of inheritance
- autosomal dominant
- autosomal recessive
- X-linked dominant
- X-linked recessive
- Codominant
- Mitochondrial
- Y-linked
- Sex- limited
Mode of inheritance
used to describe a disease state and the mode of inheritance
Dominant
- a trait is dominant if it is phenotypically expressed in heterozygotes i.e. carriers express disease
- a disease will have a dominant mode of inheritance if heterozygotes are insufficient
Recessive
- a trait or gene that is expressed only in homozygotes, and compound heterozygotes, not in carriers
- a disease will have a recessive mode of inheritance if heterozygotes produce enough/sufficient product
Codominant
-if both alleles of a pair are expressed in the heterozygous state
Types of inheritance
- autosomal inheritance- gene is located on one of the 22 pairs of autosomal chromosomes
- X-linked inheritance- genes, or traits determined by genes located on the X chromosomes
Y-linked- very few known disease genes on the Y chromosome
Mitochondrial
Autosomal Dominant Inheritance Criteria
- most affected individuals will be heterozygous
- expressed in every generation; but more likely to have reduced penetrance compared to a recessive
- half offspring of an affected individual are affected (recurrence risk of 50%)
- affected individuals usually have infected parents
- normal individuals usually don’t have affected offspring (except for reduced penetrance)
- male to male transmission indicates trait probably not X- linked
penetrence
the proportion of individuals in a population that carry a particular variant of a gene that also express an associated trait
Autosomal recessive inheritance criteria
- expect both parents of affected individuals to be carriers
- affected individuals usually have asymptomatic parents
- may appear as sporadic
- often more severe than dominant disorders
- if rare, parents more likely to be consanguinous
- recurrence risk 1 in 4
- affecteds have two mutations, are homozygous, or compound heterozygotes
Compound heterozygote
- the two mutations are in the same gene but do not need to be identical
- CF has more than a 1,900 disease-associated alleles
Recessive- chance that sibling is a carrier
-once it is clear after birth that a child is not affected, the risk that an unaffected offspring is a carrier is 2/3
X-linked recessive inheritance
- usually males affected (hemizygous)
- unless an affected male marries are carrier female, or extreme X-inactivatioin
- all daughters of affected males are carriers
- half the sons of carrier females are affected
- no male to male transmission (since pass on their y)
- many more affected males than females, mostly males more severe than females
- in “genetic lethal” disorders a significant proportion of cases will be due to new mutations
X-linked dominant inheritance
- rare
- affected males have normal sons and affected daughters
- twice as many affected females as males in the population
- most affected females will be heterozygous so half the offspring of affected females will be affected
- usually more severe or even lethal in males
- e.g. hypophosphatemic rickets
Y linked
- apart from male infertility, no/few known Y linked diseases
- only males would be affected, all sons affected
- affected males would have an affected father and all their sons would be affected and no affected daughters
- only about 78 protein-coding genes on the Y
Mitochondrial inheritance
- trait appears to be inherited exclusively through females
- all offspring of affected females will probably be affected
- highly mutable 2x compared to nuclear DNA
- variable expression and can show lack of penetrance
- not inheritied from affected males
New mutation
- disease will appear sporadic but will be familial in descendants of affected individuals but not in earlier generations or in other branches of family
- mitochondria have high mutation rate
- estimated that every Y chromosome differs by 600 base pairs from father’s Y chromosomes
- estimated that there are as many as 100-299 new base pairs changes in each person, and perhaps thousands of gene-conversion events
Mosaic
- germline and somatic mosaicism
- tissue has two or more cell lines of different genotype derived from a single zygote
- mosacism much commoner than chimerism
- patchy disease
- examples of a somatic mosaicism is lymphoma or leukemia
Germline Mosaic
- the new mutation may have arisen in the germ line and so not seen in the soma
- can account for multiple affected offspring with a dominant disease not seen in the parent
- recurrent affected offspring to unaffected parent
Blaschko’s Lines
- the lines of Blaschko visualize the clonal proliferation of two functionally different populations of cells during embryogenesis of the skin
- they represent a marker of normal development of human skin not usually visible
- originates from one zygote
Ramification of Gonadal Mosaicism
- there is still significant recurrence rate even if mutation in affected boy is not seen in mother’s blood
-mutation could be in her germline, even if not in her blood,
important in genetic counseling
Chimeric
- chimeric individual derived from cells from two different zygotes
- an example would be the recipient of a bone marrow transplant from a donor
- complete chimerism if all hematopoietic cells are from donor
- mixed chimerism if donor and recipient hematopoiesis coexist after allotransplantation
- can find a donors XX cell line in the blood of a recipient male, post transplant
Chimera
-two independent origins in two zygotes
Karen from Bosten, two of her children did not shre alleles with her. She had absorbed her DZ sister in the womb
Gene
a hereditary unit; in molecular terms, a sequence of chromosomal DNA that is required for production of a functional product
Locus
- the position of a gene on a chromosome
- different forms of the genes (alleles) may occupy the locus (an address)
Allele
-one of the alternative versions of a gene that may occupy a given locus
mutation
a permanent inherited change in the DNA
Expressivity
-the extent to which a genetic defect is expressed- mild to severe but never completely unexpressed
penetrance
-all or none expression of a genetic disease genotype
Polymorphism
-the occurance together in a population of two or more alleles, each at a frequency greater than 1%, so that the heterozygote frequency is at least 2%. Alleles with a frequency of less than 1% are called rare genetic variants
-particularly useful in linkage studies when cannot find disease causing mutations
-over 60% of all loci exhibit polymorphisms uses:
+mapping genes to chromosomes
+presymptomatic and prenatal diagnosis
+carrier detection of heterozygotes
Polymorphism types
- single nucleotide polymorphisms
- microsatellites (variable number of tandem repeats, VNTRs)
Retinitis Pigmentosa
- progressive degeneration of photoreceptor cells in the retina
- most forms cause the degeneration of rod cells which provide peripheral vision and also help in dimly lit environment- usually starts with night blindness
- sometimes central vision is affected first. With the loss of cone cells also results in disturbances in color perception
Phenocopy
- a mimic of a phenotype that is usually determined by a specific genotype, produced instead by the interaction of some environmental factor with a different genotype
- example pregnant women taking Thalidomide
Pleiotrophy
- multiple phenotypic effects of an allele or gene on tissues/systems not ordinarily thought to be related
- reflects the diversity of cell types that use a common molecular pathway for transcriptional regulation
-e.g. The seemingly unrelatedness of nearsightedness and malformation of the sternum seen in Marfan syndrome becuase of mutations of fibrillin-1 gene
Haldane’s rule requirements
- X-linked recessive
- Reduced fitness e.g genetic lethal
- negative relevant family history (Fragile X syndrome and other X-linked diseasses caused by dynamic mutations are excluded
Haldane’s rules explains…
- why not all mothers of affected boys with X-linked recessive disorders are carriers, as one would otherwise expect
- is applied to X-linked recessives when there is one affected boy and no other relevant family history of the disease and when there is reduced genetic fitness (f<1)
- classic example is DMD (f=0)
- does not apply to fragile X (triplet repeats)
Duchenne Muscular Dystrophy (DMD)
- Haldane’s rule
- X-linked recessive and if only one affected boy
- genetic lethal therefore 1/3 patients are de novo mutations and 2/3 mothers are carriers
- gonadal mosaicism- still significant recurrence rate even if mutation seen in affected boy is not seen in mother’s blood. Mutation could be in her germline, even if not in her blood
Haldane’s rule mutation
- if mutation only occurs in males (u=0) no boys will be new mutations, all mothers of affected boys are carriers (Hemophilia A inversion)
- if mutations only occur in females (v=0) then 1/2 boys will be new mutations and 1/2 of mothers will be carriers
- in Hemophilia A and Lesch-Nyhan v>u, so more mothers are carriers than when u=V
- in DMD v=u
Modes of inheritance for selected genes
Hemophilia A - XLR CF- AR Alpha1 antitrypsin def - AR DMD - AR Tay Sachs- AR Sickle cell disease - AR alpha and beta thalassemia - AR fragile x= X? HD= AD DM - AD
