genetics 2

Used to know whether different mutations that affect a characteristic occur at the same locus(allelic) or at different loci(not allelic)

• Example= development of fly wings
• Case 1: mutations are in separate genes=flies w/ wings
• Case 2: mutations are in different locations in the same gene=wingless flies
• If two wingless flies crosses yield flies w/ wings then mutations are located at two different gene loci
• If the crosses yield wingless flies then the mutations involved must be alleles

• Cross homozygous bulldog for brindle and homozygous boxer for brindle.
• If allelic then all offspring will be brindle.
• If brindle in the two breeds is due to recessive genes at different loci, then none of the offspring will be brindle.

• The inheritance of characteristics encoded by genes on sex chromosomes differs from autosomal genes
• X-linked traits are always passed on from father to daughter but never father to son, father passes on Y-linked traits to all sons

• Determined by autosomal genes, but expressed differently in males and females
• A particular trait is more readily expressed in one sex, the trait has a higher penetrance in one sex
• Example= Beards on goats are determined by a gene that is dominant in males but recessive in females. B^b

• Encoded by autosomal genes that are expressed in only one sex, the trait has zero penetrance in the other sex
• Example=Cock feathering is an autosomal recessive trait that is sex limited to males, the genotypes of males and females are the same, but the phenotypes produced are different, hh
• Another example= Male limited precocious puberty, autosomal dominant allele that is only expressed in males, P

• Not all genetic info is found in the nucleus, some is found in the cytoplasm(mitochondria)
• All cytoplasmic organelles come from the egg
• Exhibits extensive phenotypic variation

• Phenotype of offspring is determined by genotype of mother, not its own phenotype either
• Arises when substances present in the cytoplasm of the egg is crucial to early development
• Example= Shell coiling of snails, dextral(right) is dominant over sinistral(left)

• The differential expression of genetic material depending on whether it is inherited from the male or female
• Most traits are encoded by genetic info that resides in the sequences of the nucleotide bases of DNA
• Example= In mice and humans Igf2 is a gene that encodes a protein called insulin growth factor II, the offspring inherit one gene from the mother and father but the paternal copy is actively expressed and the maternal copy is silenced

• Genomic Imprinting
• Small hands&feet, poor sexual development, mental retardation, voracious appetites, obese.
• Missing a small portion of long arm on chromosome 15, the deletion of this portion is always inherited by the father.
• Lack a paternal copy of genes on long arm of chromosome 15
• Maternal copy is inactive due to imprinting

• Genomic Imprinting
• Frequent laughter, uncontrolled muscle movement, seizures, mental retardation(most do not speak), extremely thin
• deletion of long arm on chromosome 15 is inherited from mother
• Lack a maternal copy of genes on long arm of chromosome 15
• Paternal copy is inactive due to imprinting

• Addition of methyl groups
• Essential to genomic imprinting
• In mammals, methylation is erased in the germ cells of each generation and re-established in the course of gamete formation
• Sperm and eggs undergo different levels of methylation, which causes the differential expression of male and female alleles in the offspring

• A trait becomes more strongly expressed or is expressed at an earlier age from generation to generation
• Example= Mutation causing myotonic dystrophy consists of an unstable region of DNA that an increase or decrease in size as it is passed from generation to generation

• Shows anticipation
• Age of onset and severity of disease is related to the size of the unstable region.
• Due to a CAG(TNR) trinucleotide repeat
• Autosomal dominant- as TNR expansion has reached the threshold number of approximately 40 repeats
• Ubiquitous, exact function is unknown, mutation results in a deleterious gain of function
• Pathogenesis=motor abnormalities, personality changes, loss of cognition, death in midlife

• X linked dominant
• TNR=CGG, outside of the coding sequence 5' UTR
• Shows anticipation
• FMR1 promoter is hypermethylated, expressed in many cell types, most abundant in neurons, mRNA chaperone
• Moderate mental retardation in males, mild in females

• Temperature sensitive allele=an allele whose product is functional only at certain temperatures
• Example: Himalayan allele in rabbits produces dark fur at the extremities of the body when reared at 25 degrees or less. An enzyme necessary for the production of dark pigment is inactivated at higher temperatures

• Autosomal recessive allele that causes mental retardation due to a defect in the enzyme that metabolizes the amino acid phenylalanine
• When not metabolized, the phenylalanine builds up and causes brain damage in children
• Children placed on a phenylalanine low diet can prevent mental retardation and devastating effects of the disorder

• Continuous= must be described in quantitative terms
• Frequently arise as genes at many loci interact to produce the phenotype
• When a single locus with 2 alleles, there are 3 genotypes possible
• Number of genotypes encoding a characteristic is 3ⁿ, where n=number of loci with 2 alleles that influence the characteristic
• Characteristics encoded by genes at many loci are polygenic(many genes)

• One gene influences many phenotypes
• Enzyme deficiencies may yield multiple phenotypic consequences because many enzymes are involved in complex biochemical pathways
• PKU is an example, multiple phenotypic consequences result from PKU-mental retardation, light skin color, blue eye color

• A pictorial representation of a family history that outlines the inheritance of traits
• Commonly used in genetic counseling and literature
• Constructed in the process of determining modes of inheritance, linkage between genes and markers, and risk to offspring

• Blank=unaffected
• Filled=affected
• Dot=carrier
• Line=asymptomatic, may have at a later time
• Number=multiple people
• Slash=deceased
• P=proband, first identified affected person
• ?=family history unknown
• Roman numerals=generation
• Number all children&husbands&wives
• Brackets=adoption
• Identical twins=line in between two lines
• Consanguinity= double lines in between

• Requires genetic sleuthing-must recognize patterns associated with different modes of inheritance
• Certain patterns can be used to exclude the possibility of a particular mode of inheritance

• Both sexes with equal frequency
• Affected offspring are born to unaffected(heterozygous) parents=seems to skip generations
• A recessive allele may be passed for generations without the trait appearing in the pedigree
• When a recessive is rare, people outside the family are usually homozygous for the normal allele
• When an affected person mates with someone outside the family, none of the children will display the trait but they will be carriers(heterozygous)
• Consanguinity
• Example=Tay Sachs: neurological condition that leads to deafness, blindness, and death. Accumulation of a lipid

• Both sexes with equal frequency
• Does not skip generations(exception if trait arose as a new mutation and has reduced penetrance)
• Affected offspring must have affected parent, and the offspring are most likely heterozygous
• Unaffected people do not transmit the trait
• Heterozygote x unaffected=1/2 offspring affected
• If rare, most people displaying the trait are heterozygous
• Example=Familial Hypercholesterolemia&LDL receptor: defect in gene that codes for LDL receptor, too little cholesterol removed from blood. Heterozygotes have 2X normal blood LDL, homozygotes have 6X(rare)

• More frequently in males b/c males only need to inherit a single copy of the allele, females must inherit two copies to be affected
• Affected sons are born to unaffected mother who are carriers
• Skips generations
• Not passed from father to son, affected females must be homozygous&affected males are heterozygous
• Example= Hemophilia A&factor VIII: disease results from absences of a protein necessary for blood to clot. Located on the tip of the long arm of X chromosome

• Does not skip generations
• Appears in both sexes, more common in females
• Affected males pass onto all daughters and no sons
• Affected heterozygous females pass onto half their sons and half their daughters
• Females can receive this from either parent, males can only receive from mother
• Each person must have an affected parent unless mutation or not fully penetrant
• Example= Hypophosphatemia(familial vitamin D resistant rickets): defective transport of phosphate, lowered level in blood&reduced deposition in blood. (more males than females)

• Passed from father to all sons
• Does not skip generations

• Another method used to analyze the genetics of human characteristics
• Dizygotic=nonidentical twins, 2 separate eggs are fertilized by 2 sperm. (50% of genes in common, same as any sibling)
• Monozygotic=identical twins, 1 eggs fertilized by 1 sperm that splits and develops into 2 embryos

• Concordant=both members of a twin pair have the trait
• Discordant=one member of a twin pair has the trait
• Concordance=Percentage of twin pairs that are concordant for a trait
• Genetically influenced traits should exhibit higher concordance in monozygotic twins
• Concordance has genetic and environmental influence
• Discordance in monozygotic twins is also due to the environment

• Technique used to analyze human inheritance, powerful in determining the effects of genes and the environment on characteristics
• If adopted children show similarities in a characteristic with their adoptive parents, they can be attributed to environmental factors
• Comparisons of adopted persons with their adoptive parents and biological parents can help define the roles of genetic and environmental factors in determining human variation
• Example= genetic factors influence BMI

• Epigenetic modifications, depends on how genes behave
• Different methylation patterns
• Gene expression=healthy development depends upon genes being turned on and off when they are needed
• Epigenetic factors control which genes are on and off in which tissues during embryonic development
• Fetal programming=gene expression goes awry&consequences can affect long life health&even cause changes in adult health that are not detectable at birth(heart disease, diabetes, etc)

• Factors that alter how genes behave can have effects just as damaging as inheriting a gene that increases risk of disease
• These factors are called epigenetic because they control when genes are expressed
• Environmental factors can alter epigenetic control of gene expression

• Dietary and other factors can prevent the coat color gene from being turned on
• Meta-stable epiallele=epigenetic modifications at certain points on the gene are set randomly early in development
• BPA exposure alters the percentage of cells with methylation at particular sites on the Agouti mouse gene

• Linked genes do not strictly obey mendel's principle of independent assortment as linked genes tend to be inherited together
• In order to predict the results of crosses between linked genes, we need to consider the arrangement of the genes on the chromosomes
• There are genes that are linked and genes that are linked but separate independently due to crossing over

• The result of two different processes=independent assortment of genes on nonhomologous chromosomes&crossing over between linked genes
• Occurs when the F1 progeny reproduce and the combinations of its gametes differ from the parents

Each individual diploid organism possesses two alleles at a locus that separate in meiosis, with one allele going into each gamete

• In the process of separation, the two alleles at a locus act independently of alleles at the other loci
• The independent separation of alleles results in the sorting of alleles into new combinations or recombination

• Does not sort independently
• We have more genes than chromosomes
• Linked genes are in the same linkage group
• Linked genes travel together during meiosis, sort to the same gamete and are not expected to sort independently

Genes for flower color and pollen shape are near one another on the same chromosome and do not sort independently, they are linked and travel together

• Crossing over=during meiosis I, pieces of homologous chromosomes may switch or cross over and result in recombination
• The exchange of genetic material between non-sister chromatids, half are recombined and the other half is unchanged
• Genes that are close together on the same chromosome usually separate together
• As a result of crossing over, in meiosis II, genes that were once linked will assort independently
• If no crossing over takes place, then all gametes are non recombinants

• To determine linkage, set up a test cross
• Get heterozygous plant
• Then cross with a plant that is homozygous recessive

• Nonrecombinant=traits of the P generation, no new combinations
• Recombinant=new combinations

• A testcross in which one of the plants is heterozygous for two completely linked genes that results in two types of progeny, each type displaying one of the original combinations of traits present in the P generation with no recombination
• All progeny are nonrecombinant

• A testcross in which one of the plants is heterozygous for two genes that assort independently and results in four types of progeny in a 1:1:1:1 ratio, where two types are recombinant and two types are nonrecombinant in equal proportions
• Phenotypes of progeny are not the same as the parents
• 1/2=nonrecombinant&1/2=recombinant

• The percentage of recombinant progeny produced in a cross
• # of recombinant / # total progeny *100

• The arrangement of alleles on the homologous chromosomes is critical in determining the outcome of the cross
• Both wildtype on one chromosome=coupling/cis
• Each chromosome contains one wildtype(diff. phenotypes than parents but same arrangement)=repulsion/trans
• Example= australian bowfly, locus for color of thorax and locus for color of puparium are located close to each other. Result of testcross=phenotypes of offspring are the same but their numbers are different, the more common alleles in coupling are less common in repulsion, etc.

• Interchromosomal=between genes on different chromosomes and arises from independent assortment(random segregation of chromosomes in anaphase I of meiosis)
• Intrachromosomal=between genes located on the same chromosome and arises from crossing over(exchange of genetic material in prophase I of meiosis)
• Both types produce new allelic combinations in gametes

• The use of a strain of corn that had an abnormal chromosome 9 produced evidence that intrachromosomal recombination was the result of physical exchange between chromosomes
• Chromosome 9 can be visually distinguished b/c it had a densely staining knob and an extra piece of another chromosome
• Studied two loci, one for colored&colorless kernels and another for starchy&waxed kernels
• Crossed heterozygous at both loci in repulsion and homozygous for colorless and heterozygous for waxy
• Outcome confirmed that crossing over had taken place(physical exchange between chromosomes)
• Also confirmed the chromosomal theory of inheritance(genes are physically located on chromosomes)

• knowing the arrangement of alleles on a chromosome allows us to predict the types of progeny that will result from a cross entailing linked genes and to determine which will be the most abundant
• recombination frequency determines proportions of the types of offspring(divide the recombinant frequency by two)
• proportions of nonrecombinant is 100 subtracted by recombinant
• this information allows us to predict the proportions of offspring phenotypes that will result from a specific cross with linked genes
• there will be 2 types of recombinant and 2 types of nonrecombinant

• More nonrecombinant than recombinant=genes are linked
• Two options: Genes assort independently and chance produced deviation or the genes might be linked with considerable crossing over
• Use chi square test of independence

• Allows us to evaluate whether the segregation of alleles at one locus is independent of the segregation of alleles at another locus without making any assumptions about the probability of single-locus genotypes
• 1. perform testcross
• 2. construct table of observed numbers of progeny
• 3. compute expected values, if independent then equal proportions (row totals*column totals)/grand total
• 4. calculate chi-sqaure value sum(observed-expected)^2/expected
• 5. determine degrees of freedom (# rows-1)*(#columns -1) less than 0.05=not produced by chance(caused by linkage)

• For linked genes, the frequency of crossing over is proportional to the distance between them
• The farther away linked genes are from one another, the more likely they are to cross over
• The closer they are, the less likely it is they will cross over

Double crossovers between the same two genes reverses the effects of the first and restores the original parental combination of alleles

• Recombination frequencies could provide a convenient way to determine the other of genes and could be used to determine relative distances between genes
• Genetic maps=chromosome maps calculated by using recombination. some genes can be very far apart or even on different chromosomes
• Physical maps=chromosome maps calculated by using the physical distances(base pairs) along the chromosome
• Distances on genetic maps are measured in map unit, 1mu=1% recombination

• chromosomal sites that are prone to breakage
• a number of fragile sites have been identified in humans
• example=fragile x syndrome: x linked inheritance is more common in males that is the result of trinucleotide repeats(CGG)
• other fragile sites exist that are not composed of TNRs, these are not completely understood

• detailed information about DNA sequence found on individual chromosomes is available b/c of the human genome project
• geneticists can examine the # of copies of specific DNA sequences present in a cell and detect duplications, deletions, and other chromosome rearrangements
• the variations they detect are called CNVs
• common, each person may possess as many as 1000 CNVs with no observable phenotypic effect
• causes a number of diseases and disorders- associated w/ osteoporosis, autism, schizophrenia

• Change in number of individual chromosomes
• Can arise by: a chromosome being lost in mitosis/meiosis(possibly centromere being deleted), small chromosome may be lost in mitosis/meiosis(possibly result of robertsonian translocation), nondisjunction in mitosis or meiosis I/II
• 2n +/- 1, mono= 2n -1, trisomy=2n+1, tetrasomy=2n+2

Meiosis I= Improper separation in meiosis I(results in 2 trisomy and 2 monosomy), no normal gametes

Meiosis II=Improper separation in meiosis II(results in 2 normal diploid, 1 trisomy, and 1 monosomy), possibly infertility

• Nondisjunction in mitosis affects somatic cells
• Nondisjunction in meiosis affects gametes

• Seed capsules look different
• Mutant(wildtype) seed capsules result from different trisomies(2n+1)
• geneticists noticed some mutants showed unusual patterns of inheritance, some were trisomics and trisomic for different chromosome pairs

• a high % of all humans embryos conceived possess chromosome abnormalities
• more than 30% of all conceptions spontaneously abort(miscarry)-so early that the female is unaware of pregnancy
• chromosome defects are present in ~50% of miscarriages with aneuploidy accounting for most of them
• aneuploidy in humans usually produces serious development problems&results in miscarriage
• only few w/ a chromosome defect survive until birth

• Most common in humans
• Better tolerated than aneuploidy of autosomal chromosomes
• Turner&Klinfelter Syndrome

• Less common possibly due to no dosage compensation for autosomal chromosomes
• most are miscarried
• more common with smaller autosomes(21) b/c it is small and has fewer genes=less detrimental than larger chromosomes w/ more genes

• Primary down syndrome=three copies of chromosome 21
• result of random nondisjunction in egg formation-mostly maternal origin in meiosis I
• most born to normal parents, risk of conceiving a second down syndrome child is increased
• incidence increases with maternal age
• most types of aneuploidy result from maternal nondisjunction(primary oocytes remain suspended for many years and essential cellular structures required for chromosome separation may break down)

• Extra copy of chromosome 21 attached to another through translocation
• Inherited from parents that are carriers of a chromosome that has undergone a robertsonian translocation(21 translocates to 14/15)
• Persons w/ translocations do not have down syndrome, they are translocation carriers, only have 45 chromosomes
• translocation carriers have an increased chance of producing children w/ down syndrome

• 1/700 live births
• 80% of individuals die in utero
• Short life expectancy
• Variable degrees of mental retardation
• Prone to respiratory disease&heart malformations
• Children show a higher incidence of leukemia

• trisomy 18(edward syndrome) 1 in 800-severely retarded, low set ears, short neck, deformed feet, clenched fingers, heart problems, death within first year of life
• trisomy 13(patau syndrome) 1 in 15000-severe mental retardation, small head, sloping forehead, small eyes, cleft lip, extra fingers&, death by age 3
• trisomy 8- 1 in 25000-50000-mental retardation, contracted fingers and toes, low set malformed ears, prominent forehead, some have normal life expectancy

Primary (47, 21+) and Familial(robertsonian)

• many tumor cells have extra/missing chromosomes/both
• some types of tumors are associated with specific chromosome mutations including aneuploidy&chromosome arrangements
• onco=cancer
• example: CML=chronic myelogenous leukemia, due to a reciprocal translocation between chromosome 9&22, and BCR-c-ABL fusion gene that leads to unregulated cell division
• example: burkitt's lymphona=reciprocal translocation between 8&14, due to a reciprocal translocation between chromosome 8 c-MYC(oncogene) gene and a chromosome that encodes an immunoglobulin protein that leads to increased proliferation of B cells, making immunoglobulin&MYC

• change in number of chromosome sets, presence of more than 2 genomic sets
• 3n, 4n, 5n, etc
• common in plants, less common in animals(found in fish, salamanders, lizards, invertebrates)
• autopolyploidy=all chromosome sets from a single species
• allopolyploidy=chromosome sets from two or more species

• both chromosomes are inherited from the same parents-molecular techniques allow for identification
• violates rule that children w/ a recessive disorder appear only in families where both parents are carriers
• cystic fibrosis=autosomal recessive disease, some children have been born to parents where only one is a heterozygous carrier-two copies of #7 w/ defective gene inherited from the carrier parent, many cases are trisomy(1 of 3 is lost)

• nondisjunction in a mitotic division can generate patches of cells in which some cells have a chromosome abnormality
• leads to regions of tissues w/ different chromosome constitutions
• example=turner syndrome: only half of the individuals have the 45, X karyotype in all cells, most are mosaics having some normal 46, XX cells also
• example=fruit flies: develop a mix of male/female traits, sex is determined independently in each cell, sex mosaics are called gynandromorphs, in XX/XO mosaics=x linked recessive will be expressed

• results from accidents in mitosis/meiosis that produce extra sets of chromosomes
• nondisjunction of all chromosomes in mitosis in an early diploid embryo could double chromosome number and produce a autotetraploid(4n)
• autotriploid(3n) can arise when nondisjunction in meiosis produces a diploid gamete that will fuse w/ a normal haploid(1n) gamete, which produces a triploid. attempt to align in prophase I leads to random segregation=unbalanced gametes

• arises from hybridization between two species
• resulting polyploid carries chromosome sets derived from 2 or more species
• example=species I&species II each produces haploid gametes, when fused, creates a hybrid w/ 6 chromosomes, not homologous so will not pair&segregate properly during meiosis, hybrid is functionally haploid and sterile&nonviable.
• nondisjunction rarely occurs in mitotic division, leads to doubling of chromosome #=allotetraploid/amphidiploid, functionally diploid=every chromosome has a homolog

• a mutation in which a part/segment of the chromosome has been doubled
• an individual homozygous for a duplication carries the duplication on both homologous chromosomes
• an individual heterozygous for a duplication carries the duplication on one chromosome-not both(problems arise in prophase I of meiosis during chromosome pairing b/c they are not homologous for their entire length, will twist and loop for pairing)
• can detect this by visualization
• alters phenotype by altering amount of particular proteins

• a mutation in which a part/segment of the chromosome has been lost or deleted
• individuals heterozygous for deletions, the normal chromosomes must loop out during pairing in meiosis I
• phenotypic consequence depends on the genes that are located in the region deleted
• lethal when homozygous b/c all copies of the gene are missing, if heterozygous an imbalance in the gene product may result in developmental/physiological problems
• recessive alleles may be expressed when a wild type allele is deleted

• a mutation in which a part of the chromosome has been inverted(a segment is turned 180 degrees)
• paracentric=does not include centromere
• pericentric=does include centromere
• have not lost/gained genetic information, just altered the order of genes
• can have profound phenotypic effects-gene can break in 2
• homozygous=no problems arise during meiosis, homologous chromosomes can pair and separate normally
• heterozygous= gene order of homologs differ and can only align&pair if the 2 chromosomes form an inversion loop in prophase I, single crossover w/ paracentric inversion leads to abnormal gametes(1 of 4 chromatids has 2 centromeres&1 lacks a centromere and is lost) two chromosomes are NRC and the other two are nonviable

• the movement of genetic material between nonhomologous chromosomes or within the same chromosome(a segment moves to a nonhomologous chromosome or to another place on the same chromosome)
• nonreciprocal=genetic material moves from one chromosome to another w/o reciprocal exchange
• AB•CDEFG and MN•OPQRS--->
• AB•CDG and MN•OPEFQRS
• reciprocal=a two way exchange of genetic material between chromosomes
• AB•CDEFG and MN•OPQRS--->
• AB•CDQRG and MN•OPEFS

• Example of duplication
• leads to a reduced number of facets in the eye, resulting in a smaller and bar shaped eye
• results from a small duplication of the X chromosome(more duplications=smaller eye)
• inherited as an incompletely dominant x-linked trait
• homozygous females have smaller eyes than heterozygous females
• three copies=double bar
• due to unequal crossing over due to improper alignment of chromosomes that results in a duplication generating process

developmental processes often require the interaction of many genes in precise amounts-a difference in the relative amounts can result in developmental problems

the expression of a normally recessive mutation-an indication that one of the homologous chromosomes has been deleted

• when a single copy of a normal gene is not sufficient to produce a wild type phenotype
• some genes must be present in two copies for normal function

• Example of deletion
• due to a series of x-linked wing mutations in drosphila
• notch deletions behave as dominant mutations- when heterozygous for the notch deletion, flies have notched wings
• notch locus=haploinsufficient

• many genes are regulated in a position-dependent manner
• altered position may result in expression at inappropriate times or tissues
• loss of molecular control-promoters, enhancers, silencers

• inversions may have played an important role in human evolution
• G-banding patterns reveal that several human chromosomes differ from chimpanzees by only a pericentric inversion

• position effect=genes translocated to new locations may be under the control of different regulatory sequences or other genes affect their expression
• disruption of gene function=chromosomal breaks that generate translocations may disrupt gene function

• deletions frequently accompany translocations
• long arms of two acrocentric chromosomes become joined to a common centromere through a translocation, creating a metacentric chromosome w/ 2 long arms and another chromosome w/ 2 short arms(not metacentric)
• took place in a human ancestor(we are related to primates)