BY322- CH6

chromosomal aberrations

chromosomal aberrations

modifications; changes in total chromosomal number (aneuploidy, polyploidy), deletion or duplication of genes or segments of chromosome, rearrangement of genetic material within or among chromosomes. these changes can result in phenotypic variation and may be lethal or advantageous. Changes that delete, add, or rearrange substantial portions of one or more chromosomes. Include deletions, duplications, inversions, translocations. Total amount of genetic information can change. Due to one or more breaks along a chromosome, followed by loss or rearrangement. Breakages occur spontaneously. Exposure to chemicals or radiation can increase breakages. These are heritable when they occur in the formation of gametes.

euploidy

complete haploid sets of chromosomes are present

aneuploidy

organism gains/loses one or more chromosomes but not a complete set; for example monosomy: loss of a single chromosome from diploid genome

polyploidy

more than two sets of chromosomes are present. Chromosomal variation often originates from random errors during gamete production.

nondisjunction

paired homologs fail to disjoin and move to opposite poles during meiosis I or II. Leads to various conditions in humans and other organisms. (For example, Turner syndrome: 45,X; Klinefelter syndrome: 47, XXY)

monosomy

Loss of one chromosome (2n − 1) may have severe phenotypic effects. Monosomy for X chromosome occurs in humans (Turner’s syndrome). Monosomy for autosomes is usually not tolerated in humans and other animals; tolerated better in plants.

haploinsufficiency

Single copy of recessive gene is insufficient to provide life-sustaining function for organism

trisomy

extra chromosome (2n + 1) produces more viable organisms than loss of chromosome, provided that the chromosome is relatively small. The addition of a large autosome to a diploid set has severe effects; usually lethal. Trisomic plants are viable, but their phenotype may be altered. Examples: Datura (Jimsonweed): diploid 24; trisomy: 25. 12 trisomic conditions are possible. Oryza sativa (rice): diploid number is 12; trisomy: 13.Trisom results in plants with slower growth, and variable leaves, stems, and grain.

trisomy 21

down syndrome; (47, 21+). Trisomy of chromosome 21. 1/800 live births (4000-5000 births annually). 250,000 individuals currently in the United States. 12–14 characteristics; affected individuals express 6–8 on average: prominent epicanthic fold in each eye; flat face, round head, short stature with protruding, furrowed tongue; short, broad hands with characteristic palm and fingerprint pattern; cognitive disabilities, poor muscle tone; average life span 50 years; children prone to respiratory disease and heart malformations; shows higher incidence of leukemia (20 times higher). Death in older individuals often due to Alzheimer disease. Disease usually occurs earlier than in normal population

down syndrome critical region (DSCR)

Critical region of chromosome 21. Contains dosage-sensitive genes. Responsible for many of the phenotypes associated with syndrome. Extra copy of DSCR1 is also associated with decreased risk of some cancers. DSCR1 gene encodes protein that suppresses vascular endothelial growth factor (VEGF): this blocks angiogenesis (formation of new blood vessels).

human trisomies that survive to term

Patau syndrome (47, 13+), Edwards syndrome (47, 18+)

polyploidy

Instances in which more than two sets of chromosome sets are found in an organism. For example, triploids have 3n chromosomes, tetraploids have 4n chromosomes, pentaploids have 5n chromosomes, and so on. Polyploidy is relatively infrequent in animal species; it occurs in lizards, amphibians, fish, rare in mammals. Polyploidy is very common in plants. Polyploidy arises when chromosomes have replicated but the parent cell fails to divide. Instead, enters interphase: chromosome number will have duplicated. It originates in two ways: autopolyploidy and allopolyploidy

autopolyploidy

doubling within a species; Each additional set of chromosomes identical to parental species. For example, triploids AAA (where “A” is one set of chromosomes from species A). Autotriploids arise due to diploid gametes. Diploid gamete fertilized by haploid produces three sets of chromosomes. Two sperm fertilizing an ovum: triploid zygote. Autotetraploids have even number of chromosomes (4n). Theoretically more likely to be found in nature than autotriploids. In general, tetraploids are more likely to produce genetically balanced gametes and be fertile, while odd numbers of genomes result in sterile organisms.

allopolyplloidy

doubling due to hybridization between species; y results from hybridization of two closely related species. (“allo” = other). For example: AA ovum (egg) fertilized with by BB sperm; hybrid AB organism. Hybrid organism may be sterile. Sterile hybrids can undergo natural or induced chromosomal doubling, producing fertile AABB tetraploids. Since polyploid has four combined haploid genomes from two species, the organism is termed an allotetraploid. When both parental species are known, the allotetraploid organism can also called amphidiploid. Amphidiploid plants are often found in nature since they can form balanced gametes. Examples: Cotton (Gossypium) with 26 chromosomes; 13 big, 13 small; Wheat (Triticum) tetraploid 4n = 28 and hexaploid 6n = 42.

how does polyploidy arise?

Tetraploid cells can be produced experimentally from diploid cells by applying heat or cold shock to diploid cells undergoing meiosis, or by applying colchicine to somatic cells undergoing mitosis. Colchicine interferes with spindle formation.

deletion

n (deficiency): missing region of a chromosome. Portion of chromosome lost due to breaks. Small deletions usually have no adverse effect. Huge deletion portions can have severe effects. Deletion can occur near one end (terminal deletion) or from interior of chromosome (intercalary deletion). Synapsis can occur between a normal chromosome and one a deletion. Unpaired region of normal homolog must “buckle out” into deletion loop (compensation loop).

Cri du Chat syndrome

in humans: (“cry of the cat”). Segmental deletion: loss/deletion of small variable part of short arm on chromosome 5 (46, 5p-). Not inherited; results from sporadic loss of chromosomal material in gametes. Severity of syndrome varies with length of deletion. Symptoms: eerie cry similar to a cat’s meowing; abnormalities in glottis and larynx; Intellectual disability; delayed development; small head size. Occurrence: 1 in 20,000-50,000 live births.

duplications

repeated segment of chromosome. May arise through unequal crossing over between synapsed chromosomes during meiosis, or due to a replication error prior to meiosis. Three important aspects: gene redundancy, phenotypic variation, and potential for evolution

gene redundancy

duplication leads to multiple copies of genes; this may be very useful! Example: rDNA codes for ribosomal RNA (rRNA). A single copy is not sufficient; multiple copies support protein synthesis. Example: Xenopus laevis (African clawed frog): 400 copies of rDNA present per haploid. Found in single area of chromosome called nucleolar organizer region

nucleolar organizer region (NOR)

chromosomal regions that are crucial for the formation of the nucleolus.

The Role of Gene Duplication in Evolution

How do new genes arise? Susumo Ohno (1970) proposed a hypothesis that gene duplication is essential to origin of new genes during evolution. Duplicated copies can acquire mutational changes over extended periods, and assume new roles; may impart adaptive advantage to organisms, enhancing fitness. Evidence: gene families, multigene families: the genes for trypsin, chymotrypsin, myoglobin, and various forms of hemoglobin apparently arose through gene duplication. Another example: srGAP2 gene in primates. Involved in development of the brain. Humans have at least four similar copies of gene. Nonhuman primates have single copy.

CNVs: Copy Number Variants

Number of copies in duplicated sequences vary among individuals in same species. Have both positive and negative associations with disease. Pathogenic CNVs are associated with autism, Type I Diabetes, and cardiovascular disease.

inversions

rearrangement of linear gene sequence; a class of structural variation; segment of chromosome turned 180° within chromosome. Usually no loss of genetic information. Inversions require two breaks in chromosome and subsequent reinsertion of inverted segment. Chromosomal loop forms prior to breakage. Creates “sticky ends”—close together and rejoin. Pericentric inversion includes the centromere; paracentric inversion does not include centromere. Evolutionary Advantages of Inversions: alleles with inversions may be preserved generation to generation.

translocation

movement of chromosomal segment to new location in genome. Reciprocal translocation: exchange of segments between two nonhomologous chromosomes. Genetic information not lost or gained just rearranged. Does not directly alter viability of individual. Homologous chromosomes that are heterozygous for reciprocal translocation undergo unorthodox (unusual) synapsis during meiosis; genetically unbalanced gametes are produced, often leading to sterility or semisterility.

Familial Down Syndrome

Down syndrome is usually caused by nondisjunction of chromosome 21, and not expected to be inherited. Occasionally, Down syndrome runs in families. Due to translocation of chromosome 21: Familial Down Syndrome (inherited). Involves chromosomes in groups D (13-15) and G (21-22). Commonly, one parent contains a “14/21, D/G translocation,” meaning one copy of chromosome 14 contains a portion of chromosome 21; fertilization results in a zygote with 46 chromosomes but effectively three copies of chromosome 21 genes, resulting in symptoms.

Fragile Sites

chromosomes sometimes contain sites that are prone to breakage: gaps. Especially in the absence of certain chemicals, such as folic acid; apparently regions along the chromosome where chromatin not tightly coiled. In humans, there is a strong association between fragile sites and altered phenotypes, including intellectual disability and cancer. For example: Fragile-X Syndrome (FXS)

Fragile-X Syndrome (FXS)

. Individuals bearing folate-sensitive site on X chromosome. Most common form of inherited intellectual disability. Dominant trait. Affects about 1/4000 males and 1/8000 females. All males exhibit syndrome. 60% of females exhibit syndrome.

Fragile Site Gene FMR1

has trinucleotide repeat sequence CGG; contributes to Huntington disease and myotonic dystrophy: normal individual: 6–54 repeats; carriers: 55–230; fragile-X syndrome: >230 repeats lead to expression of syndrome. This is also an example of “gene anticipation:” the number of CGG repeats continues to increase in future generations

fragile sites and cancer

: Link between autosomal fragile site and lung cancer reported in 1996. FHIT gene (fragile histidine triad) located within FRA3B fragile site on chromosome 3p arm. Often altered or missing in cells taken from individuals with lung cancer. Further studies revealed normal protein product of gene was absent in cells of many other cancers (esophagus, breast, cervix, liver, kidney, pancreas, colon, and stomach)