Exam 1: Lesson 4- Chromosome and Karyotype Rearrangements

Define aneuploidy and polyploidy and know the difference

Aneuploidy= gain or loss (2n+1/2n-1) of individual chromosomes

Polyploidy= addition of one or more (3n, 4n) entire sets of chromosomes

What causes aneuploidy? most common?

Commonly:

1. mistakes in maternal meiosis

• >60% made in Meiosis 1

Less likely:

2. Mistakes in paternal meiosis (makes up 10% of down syndrome cases)

3. Mitotic errors

Why are chromosomal aberrations leading to disease and disorders?

improper amount of chromosomes leads to improper development and expression of genes

Why are autosomal numerical aberrations less tolerated by the cell/organism than aberrations in the number of sex chromosomes?

Sex chromosomes have built in mechanisms, such as X inactivation, and features, such as low gene density on Y chromosomes, that makes more or less X or Y chromosomes less impactful

Autosomes do not have these features, so more or less chromosomes influences protein production much more

What is chromosomal nondisjunction and how does it affect ploidy?

failure of homologous chromosomes or sister chromatids to separate properly during cell division

• causes aneuploidy, because it increases or decreases the number of INDIVIDUAL CHROMOSOMES (trisomy or monosomy)

What is the difference between chromosomal disjunction errors during meiosis I and meiosis II and how does each affect the cell?

Meiosis 1- homologous chromosome pairs fail to separate properly

• pulls a pair of 2 chromosomes to one side, creating 4 abnormal gametes (2 n+1 and 2 n-1)

Meiosis 2- homologous chromosomes separated properly, but then the sister chromatids in a cell separate wrong, causes 2 bad gametes (n+1 & n-1) and 2 normal gametes

What are the usual consequences of meiotic errors?

1. miscarriages

2. aneuploidy

3. reduced fertility

What is Autosomal Monosomy? Viable in mammals?

one individual chromosome from a pair of autosomal chromosomes is missing

• not viable in mammals!

• die before implantation, no pregnancy

What is the meaning of the statement ‘autosomal monosomies unmask lethal alleles’?

With only one chromosome instead of two, there is only one copy of an allele, so a recessive lethal allele that would normally not be expressed would be expressed since it is not masked by a dominant allele

Example of autosomal monosomy in mammals

Monosomy 21 in humans

• 2 cases

  • 1st caused by mistake in meiosis

  • 2nd caused by mitotic non-disjunction (monosomy 21 & trisomy 4)

What is autosomal Trisomy? Viability?

3 autosomal chromosomes instead of 2

• often lethal, some are viable

• 4% of human conceptions

Are autosomal trisomies more or less viable depending on the size of the chromosome?

Trisomies of SMALL chromosomes can be viable

Trisomies of LARGER chromosomes can be lethal

Why is autosomal trisomy more tolerated when it happens in small chromosomes than when it happens

in large chromosomes?

Small chromosomes are less gene dense

• the less gene dense a chromosome, the more likely it is to survive trisomy (less additional genetic material)

Trisomy for many different chromosomes is routinely observed in spontaneous abortions, but

monosomy is not. Why?

autosomies are usually lethal before pregnancy

trisomies survive longer so the abortion can be detected

What are the three human chromosomes that can be trisomic in liveborns? Which is the most common

among the three?

1. Trisomy 21 (down syndrome) - most common

2. Trisomy 13 (Patau Syndrome)

3. Trisomy 18 (Edwards Syndrome)

Cite and explain one possible reason for the trisomy 21 disorder. Name the syndrome

Down Syndrome

• maternal meiosis non disjunction

What is unique about Down Syndrome among the trisomies?

the ONLY autosomal trisomy where individuals MAY live longer (30-40 yo)

Features of Down Syndrome/Trisomy 21

• most spontaneously aborted

• impaired cognition

• premature aging

• heart defects

• high frequency of leukemia

• low frequency of tumors (3 copies of tumor suppressor genes)

What is a huge risk factor for having a baby with down syndrome?

Mother over the age of 35

What is a treatment thats been explored for down syndrome?

insrting XIST into trisomy 21 cell to silence one chromosome 21 into a Barr body

Features of Trisomy 13 (Patau Syndrome)

• risk factor= increased maternal age

• usually lethal in embryonic stage

• mental and motor retardation

Features of Trisomy 18 (Edwards Syndrome)

• congenital abnormalities: heart and neurological, syndactyly (fused fingers/toes… think edward scissorhands)

Spontaneous abortions with trisomy of chromosome 1 or chromosome 19 are never seen. Do they ever

occur? Explain

They rarely occur bc they almost always die before pregnancy is reached

• bc of 1 & 19 have highest gene density of all chromosomes, making trisomy much less viable because of the additional genetic information

Why are cases of polyploidy rare in mammals, birds, and reptiles?

usually fatal in embryonic stage

What are the 2 causes of Polyploidy?

1. germline event (rare)

2. somatic genome duplication (common)

What tissues does somatic genome duplication occur in? y?

tissues of high regenerative capacity like liver, placenta, bone marrow

• polyploidy used as a buffer against oxidative stress and genotoxic damage

Which germline events can lead to human polyploidy? causes?

Tetraploids (4 full chromosome sets)

• mitotic failure in embryogenesis

• cell fusion

Triploids (3 full chromosome sets)

• egg fertilized with 2 sperms

• ovum fused with polar body & fertilized by sperm

• meiosis 1 or 2 errors in oogenesis or spermatogenesis

What is the most common chromosomal abnormation in human gestation? Stats?

Triploids (3n=69), lethal

• 1-2% of all recognized conceptions

• 1-13% of spontaneous abortions/miscarriages

• 1/10,000 live births

Is tetraploidy viable?

viability is very rare… however, tretraploid/diploid mosaics are more viable bc some cells are normal

What are the consequences of numerical aberrations in sex chromosomes for the organism?

• usually viable

• sub fertility of infertility

• MILD mental and physical problems

• low number of genes

• Due to genes that escape X inactivation

How does X inactivation affect numerical abberations of sex chromosomes?

corrects some of genetic imbalance, making the offspring more compatible with life than in autosomal abnormalities

…. inactivates all but 1 X chromosome, so if theres 3, then 2 are silenced

What are the most common sex chromosome aneuploidies?

1. Klinefelter’s Syndrome

2. X-Trisomy (47, XXX)

3. X-Monosomy aka Turner’s Syndrome (45, X)

Features of Klinefelter’s Syndrome

(47, XXY)

sterile males

higher risk for x-linked autoimmune disorders

hypogonadism

Features of X-Trisomy

Trisomy= 47, XXX

• fertile females, BUT 50% sons are XXY

In X-polysomy, are genes overexpressed?

YES,

Which affects fertility more, X overdose or underdose? Why?

Underdose because overdose affects can be limited by X-inactivation… only the few genes that escape X inactivation are over expressed

What is the phenotype of Turner Syndrome (45,X) and what are the genetic consequences of having only one X?

Phenotype:

• short

• sterile (underdeveloped ovaries)

Genetic Consequences:

• Haploinsufficiency (one copy of X is not sufficient for normal function) of PAR and other genes that escape X-inactivation…. Need 2 copies of each of these genes to function properly

What is XYY Syndrome AKA? Phenotype?

Jacobs Syndrome

• subtle characteristics

• tall & very thin

• fertile w/ decreased sperm quality

What kind of mistake in meiotic cell division can lead to XYY aneuploidy?

non-disjunction in male meiosis 2

What are the types of structural chromosome abberations?

1. deletions

2. duplications

3. inversions

4. translocations

Issues during which process cause aberrations in somatic cells? germ cells?

Somatic cells= mitosis

germ cells= meiosis

What is a deletion and what are the consequences of this aberration?

loss of any genetic material

• loss of chromosome segments

• loss of gene(s) and gene products

• meiotic pairing problems

• changed phenotypes: phenotypic variation and disease

Which has a more severe effect on phenotype: deletion of the p arm of the X chromosome or deletion of the q arm? Explain.

Deletion of the q arm (long arm)

• because q has more genes that escape X inactivation… and for normal function, you need pairs of these genes… deletes one of them

In Y chromosomes, would deletion of p or q arm be worse? WHy?

q arm (long arm) bc theres 3 AZF (azoospermia factor) regions that influence fertility here… deletion of these causes infertility

In a pair of homologous chromosomes, one homolog has a deletion. What will happen in pachytene?

normal pachytene=crossing over, therefore:

• the normal homolog forms a compensation loop/deletion loop, where the deleted region should be paired

• The normal parts of the chromosomes synapse and cross over normally

Name the main consequences of duplications.

1. overdose of genetic material

2. problems in meiotic pairing

3. changes in phenotype: phenotypic variation and disease

What is the role of duplications in evolution? Give an example.

Genes duplicated in evolution to:

1. protect essential genes

2. Generate new genes (variation and adaptive mutations)

• ie. Bar eye mutation in Drosophila (eyes are a range of wide to narrow)

What are paralogous genes aka paralogs? Give an example.

• Separate genes in a species that are duplications from the same ancestral gene

• share some similarity, but have distinct gene products and function

Ie.

• duplication of starch digestion genes: AMY1 salivary amylase

  • in humans: 5-7 copies based on how much starch is in diet

  • Chimp= 2 copies, digests roots and tubers

What are inverions? Genetic consequences?

linear order of a segment is inverted 180*

• NO LOSS OF GENETIC MATERIAL

Consequences:

• changes the linear relationship/order of genes

• affects homologous pairing and crossing over in meiosis

What is the fundamental difference between deletions/duplications and inversions?

Deletions & duplications change the amount of genetic material in the genome= genome unbalanced

Inversions do not change the amount of genetic material in genome= genome balanced

What are translocations?

Exchange of genetic material between non-homologous chromosomes (=no loss or gain of genetic material)

Name the two main types of translocations

Types:

1. Non-reciprocal (1 donates to the other)

2. Reciprocal (2 swap/donate to each other)

In which way do translocations differ from deletions/duplications/inversions?

Translocations occur between two NON-homologous chromosomes,

deletions/duplications/inversions all occur within a single chromosome or between homologous chromosomes

What type of translocation has generated the Philadelphia chromosome? Which chromosomes?

HSA9/22 RECIPROCAL translocation (btw Chr 9 and 22)

What is the human Philadelphia chromosome? which genes involved?

marker chromosome in chronic myeloid leukemia

• fusion of BCR-ABL genes

  • causes continuous proliferation of cells (leukemia)

What is the dog version (homolog) of the Philadelphia chromosome?

Raleigh Chromosome

What is the difference between balanced and unbalanced gametes?

Balanced gametes= normal, complete set of genes with no gains or losses in genetic material

Unbalanced gametes= gains or losses in genetic material

What are the possible consequences of translocations for reproduction? Next generation?

normal, but sub-fertile, translocation can be inherited

next generation can be:

• normal gametes (healthy)

• balanced translocations (fertility issues)

• unbalanced translocations (unhealthy)

What kind of translocation is called ‘Robertsonian translocation’?

Fusion of 2 acrocentric chromosomes

Compare phenotypic consequences of deletions and inversions. Which are more severe? Why?

Deletions are more severe because there is a LOSS of genetic material

• gene dosage issues

• high lethality

What are fragile sites?

heritable loci on chromosomes that are prone to forming gaps or breaks when cells are exposed to chemicals which inhibit DNA replication

Give an example of a human genetic disorder associated with fragile sites. Explain its molecular

mechanism

Fragile X Syndrome (progressive neurodegenerative disorder)

—> caused by an unstable expansion of a CGG trinucleotide repeat located in the 5' untranslated region (5' UTR) of the FMR1

What are Disorders of Sex Development, also known as sex reversal conditions?

Phenotypic sex does not match what the chromosomal sex says you should be

• XX males

• XY females

What causes XX males?

SRY + (common)= SRY translocated to the X chromosome (determines male sex)

SRY - = mutation ins autosomal gene SOX9

What causes XY females? AKA?

Swyer Syndrome

SRY - = deletion or mutation in SRY

SRY + = mutations in X-linked or autosomal genes