Gene defect/ chromosome mutations

Essential terms

MutationMutation VariationVariation AneuploidyAneuploidy EuploidyEuploidy PoluploidyPoluploidy MonosomyMonosomy TrisomyTrisomy

Non disjunctionNon disjunction Sex linkedSex linked Autosomal D/RAutosomal D/R MonogenicMonogenic PolygenicPolygenic

Any form of modification = chromosomal mutation/aberration..

A Change in a Single DNA Base Can Cause A Change in a Single DNA Base Can Cause a Mutationa Mutation

Eg. Sickle cell anaemiaEg. Sickle cell anaemia

A mutation caused a GAG codon to change into a A mutation caused a GAG codon to change into a GUG codon in the gene for one of the protein GUG codon in the gene for one of the protein chains of hemoglobin chains of hemoglobin

mutation replaced the glutamic acid a2 with valine mutation replaced the glutamic acid a2 with valine Conseqences = hemoglobin stick together and Conseqences = hemoglobin stick together and

causes damage to RBC = anemia causes damage to RBC = anemia The mutation also gives some resistance to malaria The mutation also gives some resistance to malaria

in individuals with one sickle gene and one normal in individuals with one sickle gene and one normal gene gene

Inborn errors of metabolismInborn errors of metabolism

Most mutations are harmful Most mutations are harmful Caused by chemical and physical agents which Caused by chemical and physical agents which

damage DNA (UV light, x-rays, many damage DNA (UV light, x-rays, many carcinogenic & mutagenic chemicals) carcinogenic & mutagenic chemicals)

Approx. 600 genetic diseases known Approx. 600 genetic diseases known Gene therapy = correcting defective gene Gene therapy = correcting defective gene

Autosomal recessive

PKU = lacks the ability to synthesize an = lacks the ability to synthesize an enzyme to convert the amino acid enzyme to convert the amino acid phenylalanine into tyrosinephenylalanine into tyrosine

Built up Built up phenylalanine and abnormal and abnormal breakdown products in the urine and blood. breakdown products in the urine and blood.

Affects the CNS = mental impairment. Affects the CNS = mental impairment. 1 in 15,000 infants suffers from this problem. 1 in 15,000 infants suffers from this problem. PKU sufferers are placed on a diet low in PKU sufferers are placed on a diet low in

phenylalanine sufficient for metabolic needsphenylalanine sufficient for metabolic needs

Autosomal recessive Tay-Sachs DiseaseTay-Sachs Disease = degeneration of the nervous = degeneration of the nervous

system.system. Lack the ability to make the enzyme N-acetyl-Lack the ability to make the enzyme N-acetyl-

hexosaminidase, which breaks down the ganglioside hexosaminidase, which breaks down the ganglioside lipid. This lipid accumulates in lysosomes, casuing lipid. This lipid accumulates in lysosomes, casuing death to brain cells. death to brain cells.

Symptoms manifest after birth. Symptoms manifest after birth. Rarely survive past five years of age. Rarely survive past five years of age. 1 in 300,000 births) in general pop, but 1 in 3600 1 in 300,000 births) in general pop, but 1 in 3600

births among Jewsbirths among Jews One in 28 American Jews is thought to be a carrierOne in 28 American Jews is thought to be a carrier

Autosomal recessive

Albenism = the lack of pigmentation in skin, = the lack of pigmentation in skin, hair, and eyeshair, and eyes

1) the lack of enzyme along the melanin-1) the lack of enzyme along the melanin-producing pathway; producing pathway;

or 2) the inability of the enzyme to enter the or 2) the inability of the enzyme to enter the pigment cells and convert the amino acid pigment cells and convert the amino acid tyrosine into melanin.tyrosine into melanin.

Autosomal dominant

Huntington’s disease - progressive - progressive destruction of brain cells. destruction of brain cells.

The disease usually does not manifest until The disease usually does not manifest until after age 20-30.after age 20-30.

Polydactly is the presence of a sixth digit Polydactly is the presence of a sixth digit common with this trait. common with this trait.

Sex linked

Red-green colorblindness. 8% M, 0.04% F. X.Red-green colorblindness. 8% M, 0.04% F. X. Hemophilia- defective blood clotting proteinHemophilia- defective blood clotting protein Muscular dystrophy- DMD. 1 in 35,000. Muscular dystrophy- DMD. 1 in 35,000.

Muscle wasting disease.Muscle wasting disease.

Variation in number

Random error during the prod. of gametes. Random error during the prod. of gametes. Non disjunction= disruption of the normal Non disjunction= disruption of the normal

distribution of chr to gametes.distribution of chr to gametes. Consequent of this failure of separation = Consequent of this failure of separation =

variety of autosomal aneploid conds. Eg variety of autosomal aneploid conds. Eg 47XXY, 45X47XXY, 45X

Sex determination

XX , XYXX , XY Hormones affect phenotypic expressionHormones affect phenotypic expression All individuals have genes to develop into All individuals have genes to develop into

either sex. Depends on sex chromosome and either sex. Depends on sex chromosome and meiosis.meiosis.

Meiosis = creates genetic variability and Meiosis = creates genetic variability and ensures genetic consistency. Depends on ensures genetic consistency. Depends on fertilization.fertilization.

Y chromosome

Fewer genes.Fewer genes. PAR (pseudoautosomal regions)PAR (pseudoautosomal regions) MSY (male specific region of Y)MSY (male specific region of Y) SRY (sex determining region of Y) sex determinationSRY (sex determining region of Y) sex determination SRY encodes a gene product that triggers the gonadal SRY encodes a gene product that triggers the gonadal

tissue to form testes. Product = TDFtissue to form testes. Product = TDF SRY present = testes and testosterone formsSRY present = testes and testosterone forms SRY absent= gonads develop as ovariesSRY absent= gonads develop as ovaries

Susceptible genes contribute risk, but don’t cause it.contribute risk, but don’t cause it. influence the age of onset, rate of progression, or help influence the age of onset, rate of progression, or help

to protect against itto protect against it Different alleles may be associated with different Different alleles may be associated with different

degrees of susceptibility, or risk. degrees of susceptibility, or risk. The APOE gene on chromosome 19The APOE gene on chromosome 19 An individual who has two copies of one variant An individual who has two copies of one variant

allele of APOE is more likely to develop Alzheimer allele of APOE is more likely to develop Alzheimer disease at an earlier age than an individual with a disease at an earlier age than an individual with a different APOE genotype.different APOE genotype.

Variation in chromosome number

Aneuploidy = gain or loss one or more chr.Aneuploidy = gain or loss one or more chr. Monosomy = 2n – 1. eg. Monosomy = 2n – 1. eg. 45X Trisomy = 2n + 1.Trisomy = 2n + 1. Euploidy = complete haploid set of chr (x)Euploidy = complete haploid set of chr (x) Polypliody = more than 2 sets of chr.Polypliody = more than 2 sets of chr. Triploid = 3 setsTriploid = 3 sets Tetraploid = 4 sets.Tetraploid = 4 sets.

Klinefelter syndrome Aneuploidy = Extra X chromosome Aneuploidy = Extra X chromosome (XXY). 2 in 1000 male births. Lower incidence that 47XXY Sex ? Intersexuality Male genitalia and internal ducts but testes Male genitalia and internal ducts but testes

rudimentary and X produce sperm.rudimentary and X produce sperm. Tall, long arms/legs, large hands/ feet.Tall, long arms/legs, large hands/ feet. Gynecomastia and rounded hips.Gynecomastia and rounded hips. Intelligence below normal range.Intelligence below normal range. Y chromosome determines maleness.Y chromosome determines maleness.

Other abnormal karyotypes

48 XXXY48 XXXY 48 XXYY48 XXYY 49XXXXY49XXXXY 49XXXYY49XXXYY All are similar phenotypically to 47XXY.All are similar phenotypically to 47XXY. The greater number of X chromomes, the The greater number of X chromomes, the

greater the manifestations.greater the manifestations.

XXX karyotype

47XXX. 1 in 1200 female.47XXX. 1 in 1200 female. Extra X chr appears to disrupt the balance of Extra X chr appears to disrupt the balance of

gen info needed for female developmt.gen info needed for female developmt. Some may be normal, others may have Some may be normal, others may have

underdeveloped sex chrtc, sterility and mental underdeveloped sex chrtc, sterility and mental impairment.impairment.

48XXXX48XXXX 49XXXXX.49XXXXX.

47 XYY karyotype

Additional Y chromosome.Additional Y chromosome. Tall – over 6 feet.Tall – over 6 feet. In the past -Incarcerated – predispositon to In the past -Incarcerated – predispositon to

criminal acts, personality disorders and criminal acts, personality disorders and subnormal intelligence.subnormal intelligence.

High numbers in mental institutions.High numbers in mental institutions. Now –studies shows there is little consistent Now –studies shows there is little consistent

correlation between extra Y chromosome and correlation between extra Y chromosome and behaioral problem.behaioral problem.

Monosomy

Turner syndrome Turner syndrome 45X.1 in 2000 female births. Female genitalia and internal ducts, ovaries Female genitalia and internal ducts, ovaries

rudimentary.rudimentary. Short stature, broad chest, skin flaps back of Short stature, broad chest, skin flaps back of

the neck, underdeveloped breasts.the neck, underdeveloped breasts. Sex ?.Sex ?.

Partial monosomy

Segmental deletions Segmental deletions cri-du-chat syndrome. 1 in 50,000 births1 in 50,000 births Loss of small part of chr 5 = Loss of small part of chr 5 = 46-5p.Anatomical malformations – GI and cardiac

complications, often mentally challenged. Abnormal glottis and larynx develop. = infant

cryLonger the deletion = greater the impact of

physical, psychomoter and mental skills.

Trisomy 1866 J. Landon Down = Down syndrome1866 J. Landon Down = Down syndrome Trisomy 21 (47 +21). ND of chr 21.Trisomy 21 (47 +21). ND of chr 21. 1 in 800 live births.1 in 800 live births. Extra chromosome maternal? > in ageing mum.Extra chromosome maternal? > in ageing mum. 12- 14 cht. Physical, psychomoter and mental develop. 12- 14 cht. Physical, psychomoter and mental develop.

Impairment.Impairment. Mongoloid appearance = flat face, round head, short, short, Mongoloid appearance = flat face, round head, short, short,

broad handsbroad hands Short life spanShort life span Prone to RTI, heart malformations, > leukemia, alzheimerProne to RTI, heart malformations, > leukemia, alzheimer Early diagnosis – Amniocentesis and CVS.Early diagnosis – Amniocentesis and CVS.

Other trisomy Patau syndrome = = Trisomy 13 1 in 19,000 births.1 in 19,000 births. Mentally challenged, partially deaf, clrft palate, Mentally challenged, partially deaf, clrft palate,

congenital malformation of most organ system. congenital malformation of most organ system. Average survival rate = 3 mths.Average survival rate = 3 mths.

Edwards syndrome = = Trisomy 18 Infants smaller than average newborn. Infants smaller than average newborn. Congenital malf, death within 4 mths. (PneumoCongenital malf, death within 4 mths. (Pneumo))