Law: Inheritance of Complex Traits and Cytogenetics

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Continuous Pop. variance vs discontinuous Pop. variance, polygenic inheritance, and multifactorial inheritance

Single Gene Inheritance

1. variation of phenotype is based on one locus.
2. the phenotypes are "either/or"
3. phenotypes are distinct in non-overlapping distribution.
4. show discontinuous variation.

Polygenic Inheritance

1. two or more loci determine phenotype of a particular trait
2. usually shows a continuous distribution of phenotype within the population.

Discontinuous Variation

1. phenotypes that fall into two or more distinct, non-overlapping phenotypic classes.
2. Single Gene Inheritance where one locus determines the phenotype shows a discontinuous distribution.
ie) Mendel's pea plants were either short of tall.

Continuous Variation

1. a distribution of phenotypic characters that is distributed from one extreme to another in an overlapping, or continuous fashion within a population.
2. Polygenic Inheritance which is controlled by multiple loci shows a continuous distribution.
3. As population gets larger, the frequency distribution of continuous pop.variance reaches a bell shape or normal curve.
ie) height of tobacco plants distributed over a range in the population.

3 Types of Polygenic Inheritance

1. Simple Polygenic Inheritance
2. Multifactorial Inheritance
3. Multifactorial Threshold Inheritance

Simple Polygenic Inheritance

1. Two or more loci lead to phenotype.
2. no environmental influence on the phenotype
3. strictly genetic
ie) eye color and skin color

Characteristics of Simple Polygenic Inheritance

1. there are variations in phenotype but genotype follows Mendelian Inheritance.
2. traits are quantified by measuring rather than counting.
3. 2 or more genes contribute to phenotype. Each gene contributes to the phenotype, and the effect may be small.
4. phenotypic expression of polygenic inheritance varies across a wide range. This variation is best analyzed in population rather than individuals.

Assumptions made to determine the number of loci for a particular trait

1. different loci are not linked - based on independent assortment
2. dominant alleles contribute equally to the phenotype.
3. assume some baseline phenotype, each dominant allele adds equally to that phenotype
4. Recessive alleles make no contribution to the phenotype beyond the baseline.

Relationship of the number of loci and phenotypic classes

1. # of loci responsible for the characteristic will determine the number of phenotypic classes.
2. as # of loci ↑, the # of Phenotypic classes also ↑
3. as the phenotypic classes ↑, the difference between classes ↓. gives environment a better chance of influencing a phenotype.
4. equation: # of Phenotypic classes = 2n + 1,
where n= # of loci

How many phenotypic classes are there for 2 loci?

= 2(3) + 1
= 7
# of dominant alleles per genotype = 0, 1, 2, 3, 4, 5, 6

How many loci and phenotypic classes determine eye color? What colors are expressed?

1. eye color has 2 loci and 5 phenotypic classes
2. colors are brown, hazel, green, blue, and grey

Regression to the Mean

in a polygenic system, the tendency of offspring of parents with extreme differences in phenotype will exhibit a phenotype that is average of the two parental phenotypes.

Multifactorial Inheritance

1. phenotype is result of multiple loci and environmental interactions - there is no direct relationship between # of loci and phenotypic classes.
2. most complex human traits are multifactorial
3. some multifactorial characteristics do not show continuous variation - especially diseases
ie) height, weight, personality, IQ

Characteristics of Multifactorial Inheritance

1. traits are polygenic
2. each gene controlling the trait contributes a small amount to the phenotype.
3. environmental factors interact with the genotype to produce the phenotype.

Effects of Multifactorial Inheritance on Diseases

1. disease phenotype is determined by the interaction of genes and the environment
2. some genes ↑ risk and some ↓ risk
3. some environmental factors ↑ risk and some ↓ risk

Multifactorial Threshold Inheritance

1. 2 factors contribute: genetic predisposition (liability/susceptibility) and environmental trigger (non-genetic)
2. individual must inherit a minimal # of defective genes - genetic threshold; and must have exposure to a particular environment for expression.
3. ie) Type I Diabetes, congenital defects, schizophrenia

Characteristics of Multifactorial Threshold Inheritance

1. the multifactorial characteristics are not expressed until a genetic threshold is reached and an environmental trigger is present.
2. liability for genetic disorder is in a bell shaped curve
3. risk of disorder should ↓ as the degree of relatedness ↓
4. provides indirect evidence for the effect of genotype on traits and for the degree of interaction between genotype and the environment.
5. useful for predicting recurrence risks

Phenotypic Variation in a Population

1. 2 sources: different genotypes in population, and different environment in which identical genotypes are expressed.

Environment Variance

1. assuming 100% penetrance and expression
2. phenotypic variation amoung individuals with the same genotype in the population.
3. variations are due to differences in environmental factors, not genetics
ie) height of cloned trees that are planted in different areas of the forest, some trees are taller because they are closer to the water and sunlight, and others are smaller because they are more inland and don't get as much sun

Genetic Variance

1. phenotypic variation among individuals in a population where the environment remains constant or has no affect on the phenotype.
2. the variation can be directly attributed to variation in the genotypes of individuals.

Heritability

1. measures the genetic variance (how much variation is due to genetics)
2. Measured between 0-1; genetic/environmental
3. associations to phenotypic variance, not definitive
4. implication of genetic inheritance.

Limitations to Heritability

1. a calculated H-value is only valid for the population being studied under the environmental conditions present at the time.
2. only valid for a particular population

Twin Studies

1. used to look for associations in determining genetic component of multifactorial traits
2. provided indirect evidence
3. does not demonstrate cause and effect

Concordant

if both twin have phenotype

Discordance

if only 1 twin has phenotype.

Monozygous Twins

1. single fertilized zygotes split
2. genetically identical (share 1005 of genes)
3. if phenotype totally genetic than they will share all genes.
4. Concordance if phenotype is entirely genetic = H=1.0

Dizygotic Twins

1. two separate ova are fertilized by 2 separate sperm.
2. no more genetically related than siblings
3. they share 50% of genes.
4. all twins will not share phenotype
5. concordance if phenotype is the same -H=.5

Descriptive Address for chromosome

1. chromosome # (1-22, X, Y)
2. the arm (p or q)
3. region (from centromere outward)
4. Band (banding methods)

Autosomes

1. non sex chromosomes
2. Pairs 1-22

Telomeres

1. short repeated DNA sequences located at each end of chromosomes.

Type of Chromosomes based on Centomere location

1. metacentric
2. submetacentric
3. acrocentric

Metacentric

1. almost all arms are equal
2. centromere is centrally placed

Submetacentric

1. unequal arm lengths
2. centromere is placed closer to one end than the other.

Acrocentric

1. p arm is really small
2. centromere is placed very close to, but not, at one end.
ie) y chromosome

Purpose of Karyotype

1. presents the # of chromosomes present
2. 3 and type of sex chromosomes
3. presence or absence of individual chromosomes
4. nature and extent of structural abnormalities.

What does a karyotype look for?

1. abnormalities
2. either missing chromosomes or extra chromosomes
3. incorrect structure

Karyotype

complete set of chromosomes from cell that has been photographed during cell division, specifically metaphase, and arranged in standard sequence.

What cells are typically used for karyotyping?

1. leukocytes - Lymphocytes
2. fibroblasts
3. amniotic cells
4. chorionic cells

How is karyotyping done?

1. cells are mixed with mitogens which stimulate cell division - Phytohemagluttinin is used for leukocytes
2. arrest cells in metaphase, where they are aligned at metaphase plate by adding colcemid.
3. cells are centrifuged and a hypotonic solution is added to break RBC and swell leukocytes
4. Fix cells with methanol and acetic acid
5. drop cells on slide which break and form a chromosome spread.

How is chromosome banding produced?

1. produced by chemical and/or heat treatment of of chromosomes on slides.
2. reproducible and chromosome specific patterns of light and dark areas

4 Types of banding

1. G Bands - most common
2. R bands
3. Q bands
4. C bands - clinically significant, used in conjunction with G bands to id abnormalities.

G Bands

1. Trypsin is added to digest histone proteins
2. stained with giemsa
3. show patterns of dark and light bands
4. dark bands are the G bands

R Bands

1. use heat to denature proteins
2. stained with giemsa
3. get reverse G bands - light areas are the dark areas and dark areas are the light areas.
4. Dark areas are R bands with this preparation

Q Bands

1. Trypsin is added to digest histone proteins
2. stained with quinacrine mustard
3. show patterns of dark and light bands under fluorescent light
4. fluorescent band is Q band

C Bands

1.chemicals are added to digest DNA
2. stained with giemsa
3. only centromeres show dark bands

Chromosome Painting

1. chromosome specific probes have been designed - only to react to particular chromosomes
2. each autosome has its own color.

What is the purpose of prenatal diagnoses?

1. looking for chromosomal abnormalities in fetus
2. not looking for specific genetic defects

Reasons for Prenatal diagnosis

1. older maternal age because of 1° oocyte in meiosis I and maternal selection is less efficient as age progresses.
2. newborn congenital abnormalities
3. previous affected child in family
4. parents are known carriers of chromosomal abnormality
5. X-linked disorders (ascertain sex of fetus)

Amniocentisis

1. method of sampling the fluid surrounding the developing fetus (amniotic fluid) by inserting a hollow needle and withdrawing suspended fetal cells and fluid.
2. performed in 16 wks of gestation.
3. several weeks for results
4. <1% risk of complication

Chorionic Villi Sampling (CVS)

1. method of sampling fetal chorionic cells by inserting a catheter through the vagina or abdominal wall into the uterus.
2. Performed 8-10 weks of gestation
3. several days for results
4. <1% risk of complication

Polypoidy

1. chromosomal # is a multiple of haploid set
2. rarely seen in live births, more common in plants
3. seen in human spontaneous aborted fetuses

Abnormalities in chromosomal number arise from...

1. errors in meiosis during gamete formation - meiosis I and II
2. events at fertilization - dispermy
3. errors in mitosis after fertilization

Triploidy

1. three haploid sets in all autosomes and sex chromosomes (3 *23= 69 chromosomes)
2. 15-18% aborted fetuses
3. 75% of extra set is paternal - due to dispermy
4. lethal condition

Dispermy

2 sperm cells fertilize 1 ovum.

Tetraploidy

1. four haploid sets for each set of autosomes and sex chromosomes.
2. 5% spontaneous abortions
3. result from failure of cytokinesis after 1st mitotic division after fertilization.

Chimera

1. Mosaic
2. mixture of tetraploidy cells and euploidy cells
3. failure of cytokinesis after the 1st mitotic division

Causes of Tetraploidy

1. errors in cell division
2. accidents at fertilzation

Aneuploidy

1. abnormality of chromosome # that is not polploidy (does not involve complete haploid sets)
2. addition of deletion of inidividual chromosome from normal diploid set, 46.
3. usually just a single chromosome

Cause of Aneuploidy

1. nondisjunction: separation of homologous pairs in meiosis I and separation of sister chromatids in meiosis II and mitosis.
2. nondisjunction in anaphase is leading cause

Frequency of Aneuploidy occurance

1. 50% of all conceptions
2. 70% of all spontaneous births
3. 1/170 live births

Types of Aneuploidy seen in humans

1. monosomy
2. trisomy

Monosomy

1. condition in which 1 member of a chromosomal pair is missing, having 1 less than diploid # (2n-1)
2. humans = 45 chromosomes
3. autosomal monosomy is lethal usually not seen in live births

Trisomy

1. condition in which one chromosome is present in 3 copies, whereas others are diploid; having 1 more than diploid (2n+1)
2. humans = 47
3. most autosomal trisomies are lethal (spontaneous abortions)
4. does occur in live births

Trisomy 13 (Patau syndrome)

1. 1/15,000 live births
2. aver. survival rate is 6 mo.
3. sever congenital malformations
4. CNS and heart malformations lead to death
5. facial malformations, eye defects, extra toes and fingers, and feet with large protruding heels.

Trisomy 18 (Edward's Syndrome)

1. slow growth and retardation
2. 1/11,000 live births
3. aver. survival rate is 4 mo.
4. similar malformations as trisomy 13
5. more females affected - 80%
6. clenched fists, 2nd and 5th fingers overlap onto 3rd and 4th, malformed feet, heart malformations that lead to heart failure and pneumonia causes death.

Trisomy 21 (Down Syndrome)

1. 1/900 live births
2. .5% of all conceptions
3. syndrome of congenital defects
4. mental retardation, heart defects, epicanthal eye folds, brushfield spots, protruding tongue, reduced life span (< 50yrs)
5. susceptible to respiratory infection, leukemia, and ↑ risk of alzheimers

Turner Syndrome

1. sex chromosome monosomy (XO) in females
2. 45 chromosomes
3. normal intelligence
4. slightly abnormal in appearance - short stature, wide chest, rudimentary ovaries, and puffiness in the hands and feet.
5. complications - aortic constriction
6. infertile
7. 75% caused by paternal nondisjunction

Klinefelter Syndrome

1. sex chromosome Trisomy in males
2. 47 chromosomes, sometimes may include more than 2 X's
3. contain female 2° sexual characteristics
4. usually have fertility problems
5. tall stature and reduced intelligence
6. caused by 60% maternal nondisjunction
7. many cases are mosaics

XYY Syndrome

1. Trisomy - 47 (XYY) in males
2. no real significant difference
3. suspect on impulse control issues
4. normal appearance and fertility

Chromosomal Structural Abnormalities

1. correct number of chromosomes,but banding patterns indicate changes in chromosome structure
2. may lead to clinical syndromes due to gene disruption

Agents that cause chromosomal disruption

1. physical agents - ionizing radiation (x rays, cosmic rays), non-ionizing radiation (UV rays)
2. chemicals - clastogens, chemicals that damage chromosomes.
3. biological- viruses

Duplication

1. nomenclature - (dup +)
2. part of chromosome is repeated

Deletion

1. Nomenclature - (del -)
2. part of chromosome is missing
3. ie) Prader-Willi Syndrom (15q-) and Cri du chat (5p-)

Inversion

1. Nomeclature - (inv)
2. part of chromosome is rearranged and is now inverted
3. two types: cause mutations in DNA replication

Paracentric Inversion

1. breaks in the arm of chromosome and is inverted.

Pericentric Inversion

1. break in chromosome arms that include the centromere.

Prader-Willi Syndrome

1. causes weak slow growth
2. obesity as children and adults due to compulsive eating.
3. 15q-

Cri du Chat (5p-)

1. causes retardation, facial abnormalities and abnormal larynx
2. crying sounds like a cat meowing
3. affects motor and mental development
4. Genes Involved: 5p15.3 - larynx develop, 5p 15.2 - mental retardation, CTNND2 - deletion of gene causes abnormal migration of nerve cells.

Translocation

1. Nomenclature - t
2. one part of chromosome is transferred to another chromosome (non homologous exchange)

Robertsonian Translocations

1. exchange is not balanced
2. with duplicated or deleted segments that can result in embryonic death or abnormal offspring
3. some material will be lost

Example of Robertsonian Translocation

1. inherited form of Down Syndrome caused by t14/21
2. carrier is phenotypically normal
3. carrier is missing acrocentric area
4. unbalanced gametes lead to Down's in offspring
5. infertility problems
6. 5% reproductive risk

Reciprocal Translocation

1. no gain or loss of genetic material
2. balanced exchange of material
3. 2 non-homologous chromosome change parts - gametes may be imbalanced
4. can lead to monosomy or trisomy

Uniparental disomy (UPD)

1. condition in which both copies of a chromosome are inherited from one parent.
2. errors can occur in meiosis or in mitosis after fertilization

Examples of UPD

1. Prader-Willi Syndrome and Angelman Syndrome
2. can be caused by deletions in long arm of chromosome 15 or UPD
3. if both copies inherited from mother = Prader Willi syn. (male)
4. if both copies inherited from father = Angelman Syndrome (female)

Fragile Sites

1. appear as gaps or breaks at specific sites on a chromosome and are inherited as codominant traits.
2. produces breaks, deletions, and other aberrations

Fragile X Syndrome (Martin Bell Syndrome)

1. Fragile site break
2. mutation on FMR-1 gene involves repeat of CGG > 50x
3. most common form of mental retardation
4. fragile site at tip of X (q arm)
5. affects males primarily

Hardy Weinberg Equilibrium holds if that assumptions are met...

1. population must be large (>100)
2. random mating
3. no allelic selection
4. migration into or out of population is rare
5. mutation is rare
6. simple dominant/recessive inheritance

Hardy Weinberg Equilibrium

1. allele frequencies for a given locus (single gene trait) within population will stabilize and remain constant.
2. p= frequency of dominant alleles
3. q= frequency of recessive alleles
4. p +q = 1
5. p² + 2pq + q² = 1

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