Errors and Exceptions inChromosomal Inheritance

Errors

• Physical and chemical disturbances

• Errors during meiosis• Plants are more

tolerant of genetic defects than animals

Nondisjunction• Occurs when problems with

meiotic spindle cause errors in daughter cells– If tetrad chromosomes fail to

separate properly during Meiosis I

– Sister chromatids fail to separate during Meiosis II

• One gamete receives two copies of the same chromosome, another gamete receives no copy

Aneuploidy• Results when a fertilization

occurs between a normal gamete and a gamete from nondisjunction– Trisomy=have 3 copies of a

particular chromosome (2n+1)– Monosomy=have only one copy

of a particular chromosome (2n-1)

• If organisms survives, aneuploidy typically leads to a distinct phenotype

Aneuploidy

• Can also occur due to a failure of the mitotic spindle after fertilization

• If this happens early in development, the aneupliod condition will be passed to a large number of cells– Can have a substantial effect on the organism

Polyploid

• Organisms with more than two complete sets of chromosome– Normal gamete fertilizes gamete in which

there has been nondisjunction of all the chromsomes

• Results in triploid (3n)

– If a 2n zygote fails to divide after replication, a tetraploid (4n) embryo would result from future successful cycles of mitosis

Polyploidy

• Common is fairly common among plants• Much less common among animals

– Is known to occur in fish and amphibians– Plays an important role in evolution of plants– Researchers in Chile have identified a new rodent

species that may be a polyploid• Polyploids are more normal than aneuploids

– One extra missing chromosome apparently upsets the genetic balance during development than does an entire extra set of chromosomes

Polyploidy

Polyploidy in humans causes miscarriage (69, XXY)

Chromosome breakage

• Four types of changes in chromosome structure as a result of breakage– Deletion– Duplication– Inversion– translocation

Deletion

• A chromosome fragment lacking a centromere is lost during cell division

• Chromosome will be missing certain genes

Duplication

• A fragment becomes attached as an extra segment to a sister chromatid– A detached fragment may

attach to a nonsister chromatid of a homologous chromosome

– Duplicated segments will not be identical if the homologues carry different alleles

– Results in multiple copies of some genes

Inversion

• Chromosomal fragment reattaches to the original chromosome, but in the reverse orientation

Translocation

• Chromosomal fragment joins a nonhomologous chromosome

Errors• Deletions and

duplications are likely to occur during meiosis– Homologous chromatids

may break and rejoin at incorrect places during crossing over

• One chromosome loses more genes than it receives

• Products of a nonreciprocal crossover are one chromosome with a deletion and one with a duplication

Large deletions

• A diploid embryo that is homozygous for a large deletion or a male with a large deletion on its X chromosome is usually missing many essential genes– Usually lethal

• Duplications and translocations are typically harmful

• Reciprocal translocation or inversion can alter phenotype because a gene’s expression is influenced by its location among neighboring genes

Human disorders

• Several serious human disorders are due to alterations of chromosome number and structure

• Aneuploid zygotes– Frequency is quite high– Most are lethal (spontaneously aborted)– Severe developmental problems result from

an imbalance among gene products

Aneuploid

• Certain aneuploid conditions upset the balance less– Making survival possible– Surviving individuals have a set of symptoms

(syndrome)• Characteristic of the type of aneuploidy

– Can be diagnosed by fetal testing before birth

Down Syndrome

• Trisomy 21– Characteristic facial features– Short stature– Heart defects– Susceptibility to respiratory infection– Mental retardation– Increased risk of developing leukemia– Increased risk of developing Alzheimer’s disease– Most are sexually underdeveloped and sterile

Down syndrome

• 1 in 700 children in the US• Nondisjunction during gamete

production in one parent• Frequency increases with

maternal age– May be linked to age-dependent

abnormality in the spindle checkpoint during meiosis I, leading to nondisjunction

• Other trisomies also increase with maternal age, but these rarely for these infants to survive long

Nondisjunction of sex chromosomes

• Upsets genetic balance less severely than autosomal aneuploidy– Because the Y contains only a few genes– Extra copies of X become Barr Bodies in

somatic cells

Disorders resulting from Gamete nondisjunction

• XXY=Klinefelters– 1 in 2000 births– Have male sex organs– But abnormally small testes and are sterile– Extra X is inactivated, but some breast

enlargement and other female characteristics are common

– Normal intelligence

Multiple Chromosome Defects: Klinefelter’s Syndrome (46, XXY)

Trisomy X

• XXX– 1 in 2000 live births– Healthy females– Both extra X are reduced to Barr body

Monosomy XTurner Syndrome

• XO– 1 in 5000 live births– Only known viable monosomy in humans– Phenotypically female– Sterile, sex organs do not mature– With estrogen therapy, secondary sex

characteristics form– Most are of normal intelligence

Multiple Chromosome Defects: Turner’s Syndrome (46, XO)

Alterations of chromosomes• Can also cause human

disorders• Deletions (even in

heterozygotes) can cause severe problems

• Cri du chat– Specific deletion in

chromosome 5– Mentally retarded, small

heads, unusual facial features, cry sounds like a mewing of a distressed cat

– Fatal in infancy or early childhood

Other translocations• Between nonhomologous chromosomes

– Implicated in certain cancers• Chronic myelogenous leukemia (CML)• Large fragment of chromosome 22 switches places with

a small fragment from tip of chromosome 9• The short, easily recognized chromosome 22 is called

the Philadelphia Chromosome

Figure 15.16

Normal chromosome 9Reciprocal

translocation

Translocated chromosome 9

Philadelphiachromosome

Normal chromosome 22 Translocated chromosome 22

Genomic imprinting

• Phenotypic effects of some mammalian genes depend on whether they are inherited from the mother or father– Affects a few dozen identified genes (may be

many more)– Not necessarily sex linked (may or may not lie

on the X chromosome)– Occurs during formation of gametes– Results in silencing of certain genes

• Imprinted genes are not expressed

Imprinting

• Some zygote genes are maternally imprinted• Some are paternally imprinted

– Imprints are transmitted to all body cells during development

– If maternally imprinted, then only parental allele is expressed

– If paternally imprinted, then only maternal allele is expressed

• Patterns of imprinting are characteristic for a given species

Insulin-like growth factor

• Igf2– One of the first imprinted genes identified– Required for normal growth– Only the paternal allele is expressed– Evidence elucidated by crosses between wild type

mice and dwarf mice homozygous recessive for mutation in Igf2

• Phenotypes of heterozygotes differ, depending on whether the mutant allele comes from the mother or father

• Igf2 allele is imprinted in eggs, turning off expression of imprinted allele

• In sperm Igf2 is not imprinted and functions normally

Genomic Imprinting: An Example

What is genomic imprinting?

• Addition of methyl (-CH4) to cytosine nucleotides on one of the alleles

• Hypothesis is that methylation silences an allele– Other mechanisms may lead to silencing of

imprinting genes

• Most of the known imprinted genes are critical for embryonic development

In experiments..

• Mice embryos that inherit both copies of certain chromosomes from the same parent die before birth (regardless of whether parent is male or female)

• Normal development requires embryonic cells have one (and only one)active copy of certain genes

• Abnormal imprinting is associated with abnormal development and certain cancers

Extranuclear genes• Small circles of DNA in

mitochondria and chloroplasts– Mitochondria and

chloroplasts reproduce themselves and pass their genes to daughter organelles

• Do not display mendelian inheritance– Genes are not distributed

to offspring according to the same rules of nuclear chromosome distribution

First observed

• By Karl Correns in 1909– Inheritance of patches of yellow or

white on the leaves of a green plant– Determined the coloration of

offspring was determined by only the maternal parent

– Coloration patterns are due to genes in plastids inherited via the ovum (NOT via the sperm)

Mitochondrial genes

• A zygote inherits all its mitochondria from the ovum.

• All mitochondrial genes in mammals demonstrate maternal inheritance

Human Disorders due to mitochondrial DNA mutations

• Primarily impact ATP supply by producing defects in Electron transport chain or ATP synthase

• Tissues requiring high energy needs may suffer energy deprivation

• Mitochondrial myopathy– Weakness, intolerance of exercise, muscle

deterioration

• Other mitochondrial mutations may contribute to diabetes, heart disease and other diseases of aging

Think about it:

Distinguish between sex-linked disorders and sex chromosome

disorders.

Think about it:

• Can you identify the chromosome abnormality in this karyotype?

• Is this individual a male or a female?

Think about it:

• Can you identify the chromosome abnormality in this karyotype?

• Is this individual a male or a female?

Think about it:

The ABO blood type locus has been mapped on chromosome 9. A father

who has blood type AB and a mother who has blood type O have

a child with trisomy 9 and blood type A. Using this information, can you

tell in which parent the nondisjunction occurred? Explain

your answer.