genetics 1 Flashcards
proband
The affected member through whom a family with a genetic disorder is brought to attention
consultand
the person who brings the family to attention (can be affected or unaffected)
consanguineous matings
Couples who have >1 known ancestors in common r
Single-gene disorders
(also called Mendelian disorders) often present with characteristic and recognizable patterns in pedigrees. These are important patterns to recognize clinically
phenotypes
the observable expression (of a genotype) as a morphological, clinical, cellular, or biochemical trait
Genotype
the set of alleles that make up his or her genetic constitution (usually we are talking about a single locus)
meiosis
a type of cell division in which diploid germ line cells give rise to haploid gametes. Prior to the initiation of meiosis, cells complete one round of DNA replication. The cells then undergo two successive rounds of chromosome segregation without an intervening round of DNA replication. Thus, the chromosome content is reduced from 4n to 2n in the first meiotic division, and from 2n to n in the second meiotic division, where n is the euploid number of chromosomes.
Two key differences between mitosis and meiosis
i) paternally- and maternally-derived homologous chromosomes pair at the onset of meiosis (prophase I), whereas the two homologs segregate independently in mitosis; and ii) reciprocal recombination events between maternal and paternal sister chromatids generate chiasmata (physical linkages) between homologs. In contrast, recombination between homologs is rare during mitosis.
Meiotic prophase I
Maternal and paternal homologs of each chromosome become paired or synapsed along their entire lengths, forming structures known as “bivalents”. This process requires the formation of a proteinaceous structure called the synaptonemal complex, which promotes inter-homolog interactions. Reciprocal recombination events occurring at this stage generate physical links between homologs. These attachments, or crossovers, are also known as chiasmata. On average, 2-3 crossovers occur on each chromosome, resulting in genetic reassortment between chromosomes. Importantly, the synaptonemal complex disassembles at the end of prophase I, and bivalents are therefore held together only by chiasmata.
first meiotic division
homologs are segregated to opposite poles of the cell. Meiosis I is the most error-prone step of the process, and chromosome nondisjunction at this stage is the most frequent mutational mechanism in humans.
Meiosis II
Unlike mitosis, chromosomes undergo a second round of segregation in meiosis II without an intervening round of DNA replication. Meiosis II is very much like a mitotic division.
Genetic consequences of meiosis
reduction in chromosome number from diploid to haploid, random segregation of homologous chromosomes, giving ~8x106 (or 223 ; 2 homologs for each of 23 chromosomes) different possibilities, random shuffling of genetic material due to crossover events, resulting in a vast increase in genetic variability from the above estimate
Mitosis
one round of chromosome segregation, resulting in daughter cells identical in chromosomal content to the parental cell, DNA replication precedes each round of chromosome segregation, no pairing of homologous chromosomes, infrequent recombination, centromeres on paired sister chromatids segregate at each anaphase, occurs in somatic cells and in germ line precursor cells prior to entry into meiosis
Meiosis
two rounds of chromosome segregation without an intervening round of DNA replication, parental cells must be diploid and the chromosome number is halved in the resultant cells, requires the pairing of homologous chromosomes and recombination for its successful completion, centromeres on paired sister chromatids divide only at anaphase II in a normal meiosis,occurs only in the germ line
Metacentric
the centromere is located in the middle of the chromosome, such that the two chromosome arms are approximately equal in length.
Submetacentric
the centromere is slightly removed from the center.
Acrocentric
the centromere is near one end of the chromosome. There are five in the human genome. In an acrocentric chromosome the p arm contains genetic material including repeated sequences such as nucleolar organizing regions, and can be translocated without significant harm, as in a balanced Robertsonian translocation. They also have distinctive masses of chromatin known as satellites attache dto their short arms by narrow stalks. These stalks contain hundresds of copies of genes encoding ribosomal rna and a variaty of repeptive sequences.
telocentric
the centromere is at one end and only have a single arm. This does not occur in normal human karyotypes.
cytogenetically
a branch of genetics that is concerned with the study of the structure and function of the cell, especially the chromosomes. It includes routine analysis of G-banded chromosomes, other cytogenetic banding techniques, as well as molecular cytogenetics such as fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH).
Short arm locations
p (petite)
long arm locative
q
chromosomal regions
Each chromosome is considered to be divided into different regions labeled p1, p2, p3; q1, q2, q3 etc., counting outwards from the centromere. Chromosomal regions are defined by specific landmarks (distinct morphological features) that include telomeres, centromeres, and banding patterns. Depending on the level of microscopic resolution, regions are subdivided into bands labeled p11 (pronounced “one-one”, not eleven!), p12, p13, and then p11.1 (p one-one point one), again counting outwards from the centromere. The centromere is designated “cen” and the telomere “tel”. It is conventional to refer to relative chromosomal locations in terms of proximity to the centromere. Thus, proximal 2q means the segment of the long arm of chromosome 2 that is closest to the centromere, and distal Xp means the portion of X most distant from the centromere, and therefore closest to the telomere.
Triploidy
Triploidy is a rare chromosomal abnormality. Fetuses with Triploidy, or Triploid Syndrome, have an extra set of chromosomes in their cells. One set of chromosomes has 23 chromosomes and is called a haploid set. Two sets, or 46 chromosomes, are called a diploid set. Three sets, or 69 chromosomes, are called a triploid set.
Trisomy
the situation in which an extra copy of an entire chromosome is present in the cell. There is variation among trisomies with regard to the parent and meiotic stage of origin of the additional chromosome. In general, however, maternal errors in the first meiotic division predominate among almost all trisomies. In addition, increasing maternal age, or more exactly, the proximity to menopause, is thought to be a significant risk factor for most, if not all, trisomies.
Monosomy
the condition in which a cell lacks one copy of a chromosome. Autosomal monosomies result in early embryonic lethality, although individuals that are monosomic for the X chromosome (45,X; Turner syndrome) survive. In contrast, most trisomies are compatible with at least some fetal development, but often result in spontaneous abortion.
Mosaicism
the presence of two or more populations of cells with different genotypes in one individual who has developed from a single fertilized egg. Mosaicism can result from various mechanisms including chromosome non-disjunction, anaphase lag and endoreplication. Anaphase lagging appears to be the main process by which mosaicism arises in the preimplantation embryo. Mosaicism may also result from a mutation during development which is propagated to only a subset of the adult cells.
Marker chromosome
A small chromosome containing a centromere occasionally seen in tissue culture, often in a mosaic state (present in some cells but not in others). A marker chromosome may be of little clinical significance or, if it contains material from one or both arms of another chromosome, may create an imbalance for whatever genes are present; assessment to establish clinical significance, particularly if found in a fetal karyotype, is often difficult. They are usually in addition t normal chromosome complement and are called supernumerary chromosomes or extra structurally abnormal chromosomes. larger marker chromosomes invariably contain some material from one or both chromosome ars creating an imbalance for whatever genes are present. many marker chromosomes lack indentifiable telomeric sequences and are likely to be small ring chromosomes (are created when there are two breaks followed by a fusion)
Translocation, reciprocal
are usually an exchange of material between nonhomologous chromosomes.
Translocation, Robertsonian
a type of reciprocal translocation caused by breaks at or near the centromeres of two acrocentric chromosomes. The reciprocal exchange of parts gives rise to one large metacentric chromosome and one extremely small chromosome that may be lost from the organism with little effect because it contains so few genes. The resulting karyotype in humans leaves only 45 chromosomes, since two chromosomes have fused together.
causes of deletion
it may orginiate simply by chromosome breakage and loss of the acentric segment or from unequal crossing over between misaligned homologous chromosomes or sister chromatids. It can also occur from abnormal segregation of a balanced translocation of inversion
causes of duplications
can originate by unequal crossing over or by abnormal segragation from meiosis in a carrier of a translocation or inversion.
Terminal deletion
a deletion that occurs towards the end of a chromosome.
interstitial deletion
a deletion that occurs from the interior of a chromosome.
breakpoint
As a cell divides, during metaphase, the chromosomes all line up in the center of the cell. Microtubules attach to the chromosomes and pull them apart, so half the DNA ends up in each daughter cell. Before the DNA gets pulled apart, the chromosomes are free to recombine, so your chromosome 5, for example, is actually a mix of chromosome 5 from your mother and father. During recombination, the chromosomes must break and reattach. “Chromosomal breakpoints” refers to these places where they break. Occasionally something goes wrong and the reattachment happens in the wrong place…this can spell disaster. Usually the term “chromosomal breakpoints” is used in the context of some abnormality.
Karyotype
the number and appearance of chromosomes in the nucleus of a eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism. The normal human karyotypes contain 22 pairs of autosomal chromosomes and one pair of sex chromosomes. Normal karyotypes for females contain two X chromosomes and are denoted 46,XX; males have both an X and a Y chromosome denoted 46,XY. Any variation from the standard karyotype may lead to developmental abnormalities.
Aneuploidy
the condition in which cells contain an abnormal chromosome number. This condition is frequently the result of chromosome nondisjunction, the missegregation of chromosomes at metaphase in either mitosis or meiosis, such that daughter cells receive extra or fewer than the normal number of chromosomes. The most common mechanism is meiotic chromosome nondisjunction. Increased rates of meiosis I nondisjunction are associated with aberrations in the frequency or location, or both, of recombination events in meiosis I. Maternal age is also another contributing factor to aneuploidy.
Monosomy
the condition in which a cell lacks one copy of a chromosome
Down syndrome
(trisomy 21) is the most common human chromosomal disorder ascertained in liveborn infants (~1/900). In more than 95% of trisomy 21 cases, the additional chromosome 21 is maternal in origin, and dosage studies indicate that nondisjunction during maternal meiosis I is by far the most common cause.
Mechanism of nondisjunction
Meiotic recombination events (crossovers) are essential for tethering homologous chromosomes during the first meiotic division. Not surprisingly, disturbances in the recombination pathway are associated with abnormalities in chromosome segregation in the first meiotic division. Nondisjunction events are related to the positioning of chiasmata; crossover events that occur too near or too far from the centromere increase chromosome nondisjunction. Centromere-distal exchanges are less effective in ensuring appropriate spindle attachment and separation of paired homologs in meiosis I; centromere-proximal or excessive numbers of exchanges lead to entanglement of paired homologs in MI that then undergo reductional division leading to what appears to be MII errors. Nondisjunction events are also related to the frequency of crossover events. The reduction or absence of recombination events increases the likelihood of nondisjunction. Nondisjuction occurs more frequently in females
mitotic mutations
results in mesaicism as either somatic mutations, can also result in germ line mutations because germ line cells under go rounds of mitotic division before they undergo meiosis
meiotic mutations
result in germ line mutations
Meiotic Recombination
~2-3 cross-over events/pair of homologous chromosomes, Each cross-over, also called a chiasma, generates a physical link between homologues that is critical for normal chromosome disjunction (segregation). Cross-overs also occur within pseudoautosomal regions of sex chromosomes during male meiosis. recombination occurs between the two non sister chromosome. The cross over are the only thing holding together the homologues chromosome pairs. In XY complex there is a pseudohomologous region that holds together this region
synaptonemal complex
a highly ordered proteinaceous structure that assembles at the interface between aligned homologous chromosomes during meiotic prophase. The SC has been demonstrated to function both in stabilization of homolog pairing and in promoting the formation of interhomolog crossovers (COs).
Genetic variability
arises from recombination during meiotic prophase I and independent assortment of maternal and paternal chromosomes
chiasmata
are specialized chromosomal structures that hold the homologous chromosomes together until anaphase I. They are formed at sites where programmed DNA breaks generated by Spo11 undergo the full recombination pathway to generate crossovers. Only one chiasma per pair of homolog arms is needed to hold homologous chromosomes together during meiosis I.
cohesions
maintained between sister chromatid arms during prophase of meiosis I
reductional division
The first cell division in meiosis, the process by which germ cells are formed. In reduction division, the chromosome number is reduced from diploid (46 chromosomes) to haploid (23 chromosomes). Also known as first meiotic division and first meiosis.
Nondisjuction during meiosis I
100% gamets have abnormalities. Increased rates of meiosis I nondisjunction are associated with aberrations in the frequency or location, or both, of recombination events in meiosis I.
Nondisjuction during meiosis II
50% of gametes have abnormalities
idiogram
A diagrammatic representation of chromosome morphology characteristic of a species or a population.
g banding
completed using giemsa dye, higher AT bases= giemsa dark
Maternal Age Effect
The precise cause of the maternal age effect remains controversial. Two models are two- hit and terminilization
Polyploidy
the heritable condition of possessing more than two complete sets of chromosomes. Polyploids arise when a rare mitotic or meiotic catastrophe, such as nondisjunction, causes the formation of gametes that have a complete set of duplicate chromosomes. Diploid gametes are frequently formed in this way. When a diploid gamete fuses with a haploid gamete, a triploid zygote forms, although these triploids are generally unstable and can often be sterile. it is believed that 10% of spontaneous abortions in humans are due to the formation of polyploid zygotes.
“two-hit” theory
suggests that several events may be responsible for increased aneuploidy in the eggs of women approaching menopause. The first “hit” is diminished recombination, caused either by a lack of chiasma or their mislocalization, resulting in a chromosome more susceptible to possible nondisjunction. The ability of oocytes to successfully complete chromosome segregation in the presence of unfavorable recombination events is thought to diminish over time, representing the second “hit” in this model.
terminalization theory
A second model suggests that the degradation of cohesin complexes over the course of the extended meiosis I arrest in oocytes results in precocious separation of homologs. In meiosis, the cohesin complex has dual functions: ensuring cohesion between sister chromatids and maintaining inter-homolog associations distal to the site of crossovers. Both activities are crucial in orchestrating the segregation of homologs at the first meiotic division. It is thought that there is little or no new deposition of the proteins of the cohesin complex during the extended meiosis I arrest in females. Therefore, the age-related degradation of cohesion established during fetal development has been postulated to allow “terminalization” to occur, the movement of chiasmata toward the ends of the homologs. Terminalization eventually leads to the premature separation of homologs and/or sister chromatins, resulting in aneuploidy.
dispermy
The penetration of an ovum by two spermatozoa.
tetraploid
having a chromosome number that is four times the basic or haploid number.
Edwards syndrome
Trisomy 18, also called Edwards syndrome, is a chromosomal condition associated with abnormalities in many parts of the body. Individuals with trisomy 18 often have slow growth before birth (intrauterine growth retardation) and a low birth weight. Affected individuals may have heart defects and abnormalities of other organs that develop before birth. Other features of trisomy 18 include a small, abnormally shaped head; a small jaw and mouth; and clenched fists with overlapping fingers. Due to the presence of several life-threatening medical problems, many individuals with trisomy 18 die before birth or within their first month. Five to 10 percent of children with this condition live past their first year, and these children often have severe intellectual disability.
Patau syndrome
Trisomy 13, also called Patau syndrome, is a chromosomal condition associated with severe intellectual disability and physical abnormalities in many parts of the body. Individuals with trisomy 13 often have heart defects, brain or spinal cord abnormalities, very small or poorly developed eyes (microphthalmia), extra fingers or toes, an opening in the lip (a cleft lip) with or without an opening in the roof of the mouth (a cleft palate), and weak muscle tone (hypotonia). Due to the presence of several life-threatening medical problems, many infants with trisomy 13 die within their first days or weeks of life. Only five percent to 10 percent of children with this condition live past their first year.
Klinefelter syndrome
Phenotypes include tall stature, hypogonadism, under-
developed secondary sexual characteristics, gynecomastia, usually infertile, some degree of language impairment. Incidence is 1/1000 live male births, half of cases result from errors in paternal meiosis I due to failure of recombination in pseudoautosomal regions. About 15% of cases result from mosaicism, and the most common mosaic karyotype is 46,XY/47,XXY
Turner syndrome
≥99% of 45, X fetuses abort spontaneously. Incidence is 1/4000 live female births,and most frequent karyotype is 45,X; 25% of individuals with Turner syndrome are mosaic. Phenotypes include short stature, webbed neck, edema of hands and feet, broad shield-like chest, renal and cardiovascular anomalies, and a failure in ovarian development.
Mosaicism
the presence of at least two genetically different cells in a tissue that is derived from a single zygote. This condition results from mutations arising in single cells in either prenatal or postnatal life, generating clones of cells genetically different from the original zygote. The number of cells containing the mosiasim depends on how early in post-zygotic mitotic division. Human genomic instability occurs in cells dividing either meiotically or mitotically. Mutations that occur during mitotic cell cycles are passed on to daughter cells and distribute within organisms according to their timing and cellular phenotypes. Mosaic phenotypes are highly variable and the effects of mosaicism are very difficult to predict. effects on development vary with the timing of the nondisjunction event, the nature of the chromosomal abnormality, and the tissues affected. Types include polyploid and aneuploid mosaics Somatic chromosomal errors that occur during development lead to chromosomal mosaicism. Examples: 47,XX +21/46,XX (mosaic Down syndrome); 46, XX/46,XY (true hermaphroditism). Somatic chromosomal mutation is a common mechanism through which cell lines come to overexpress oncogenes or lose tumor suppressor genes. Mosaic parents with mild phenotypes can have fully affected offspring.
Germ line mosaicism
exists when a somatic mutation occurs early in development and generates a mutant sub-population of germ cells. Human female and male germ line cells undergo approximately 30 or 50 mitotic cell divisions, respectively, before differentiating into stem germ cells that then enter meiosis. A germ line mosaic individual is therefore capable of conceiving multiple offspring with apparent new (de novo) mutations. Thus, the recurrence risk for any genetic disorder is never “zero”. In addition, germ line mosaicism has been demonstrated in nearly every human Mendelian and chromosomal disorder and has important implications for genetic counseling.
Sex Chromosome Abnormalities
Aneuploidies are relatively common, and are more frequent than structural rearrangements. In general, the phenotypes associated with sex chromosome abnormalities are less severe than autosomal aneuploidies due to X chromosome inactivation and the relatively low number of genes that reside on the Y chromosome. Again, defects in sex chromosome number can often be traced to errors in maternal meiosis as a result of increased maternal age.
holoprosencephaly
Holoprosencephaly is a disorder caused by the failure of the prosencephalon (the embryonic forebrain) to sufficiently divide into the double lobes of the cerebral hemispheres. The result is a single-lobed brain structure and severe skull and facial defects. In most cases of holoprosencephaly, the malformations are so severe that babies die before birth. In less severe cases, babies are born with normal or near-normal brain development and facial deformities that may affect the eyes, nose, and upper lip. This can occur in patau syndrom
Polydactyly
Having extra fingers or toes (6 or more) can occur on its own. There may not be any other symptoms or disease present. Polydactyly may be passed down in families. This trait involves only one gene that can cause several variations. Some genetic disease that can lead to this are rubinstein taybi syndrome and trisomy 13
Omphalocele
an opening in the center of the abdominal wall where the umbilical cord meets the abdomen. Organs (typically the intestines, stomach, and liver) protrude through the opening into the umbilical cord and are covered by the same protective membrane that covers the umbilical cord. Edwards and Patau syndrome are associated with it
Hypertonicity
an increased tension of the muscles, meaning the muscle tone is abnormally rigid, hampering proper movement. Neonatal or congenital hypertonia, on the other hand, is usually a result of severe brain damage. Infants experiencing hypertonicity often have joint contractures and general discomfort as well as difficulty feeding.
47,XYY Syndrome
Indistinguishable physically or mentally from normal males and are usually fertile. Incidence is 1/1000 live male births, results from errors in paternal meiosis II, producing YY sperm. Increased risk of behavioral and educational problems, delayed speech and language skills. Not associated with criminality, as was originally hypothesized
Random variation
Random genomic variation is the fuel of evolution. Random variation in a highly ordered structure = almost always deleterious consequences. Genetic disease is the price we pay as a species to continue to have a genome that can evolve, i.e., that can adapt to new and changing environments
Findings from the first human genome sequence
The human genome is not static; it is dynamic and continues to evolve. There are ~30 new mutations occur in each individual. Shuffling of regions at each meiosis due to recombination. Can produce somatic DNA changes as well as germ-line DNA changes. There is no “one” human genome; there are many human genomes because of single nucleotide polymorphism (SNP). Average of 1 SNP every 1000 bp between any two randomly chosen human genomes. Genome is not organized in a random manner: Gene-rich regions/chromosomes (e.g. Chr 19), Gene-poor regions/chromosomes (e.g. Chr 13, 18, 21), Stable regions: majority of genome, Unstable, dynamic regions; many are disease-associated (e.g. SMA (Chr 5q13); DiGeorge syndrome (Chr 22q); 12 diseases (1q21)), GC-rich regions (38% of genome), AT-rich regions (54% of genome), Clustering (i.e. non-random distribution) of GC-rich and AT-rich regions is basis for chromosomal banding patterns (cytogenetics, karyotype analysis)
satellite DNAs
consists of very large arrays of tandemly repeating, non-coding DNA. Satellite DNA is the main component of functional centromeres, and form the main structural constituent of heterochromatin. Some are in different parts of genome, e.g. used as the basis for cytogenetic banding. Some (a particular pentanucleotide sequence) are found as part of human-specific heterochromatic regions on the long arms of Chr 1, 9, 16 and Y (hotspots for human-specific evolutionary changes), “α-satellite” repeats (171 bp repeat unit) found near centromeric region of all human chromosomes; may be important to chromosome segregation in mitosis and meiosis.
Dispersed repetitive elements
Interspersed (or dispersed) DNA repeats (interspersed repetitive sequences) are copies of transposable elements interspersed throughout the genome.
The Alu family
The Alu family is a family of repetitive elements in the human genome. Modern Alu elements are about 300 base pairs long and are therefore classified as short interspersed elements (SINEs) among the class of repetitive DNA elements. The typical structure is 5’Part A- A5TACA6 -Part B - PolyA Tail - 3’, where Part A and Part B are similar nucleotide sequences, but of opposite direction. Expressed another way, it is believed modern Alu elements emerged from a head to tail fusion of two distinct FAMs (fossil antique monomers) over 100 mkya, hence its dimeric structure of two similar, but distinct monomers (left and right arms, and in opposite directions) joined by an A-rich linker. The length of the polyA tail varies between Alu families. Alu elements are a common source of mutation in humans, but such mutations are often confined to non-coding regions where they have little discernible impact on the bearer.However, the variation generated can be used in studies of the movement and ancestry of human populations, and the mutagenic effect of Alu and retrotransposons in general has played a major role in the recent evolution of the human genome. There are also a number of cases where Alu insertions or deletions are associated with specific effects in humans, such as cancer and diabetes
Long Interspersed repetitive Elements
a group of non-LTR retrotransposons which are widespread in the genome of many eukaryotes. A typical L1 element is approximately 6,000 base pairs long and consists of two non-overlapping open reading frames (ORF) which are flanked by UTR and target side duplications. In the first human genome draft the fraction of LINE elements of the human genome was given as 21% and there war 300 bp related members and 500,000 copies in genome
Retrotransposons
also called transposons via RNA intermediates) are genetic elements that can amplify themselves in a genome and are ubiquitous components of the DNA of many eukaryotic organisms. They are one of the two subclasses of transposon, where the other is DNA transposon, which does not involve an RNA intermediate. They are particularly abundant in plants, where they are often a principal component of nuclear DNA.
Short Interspersed Elements
short DNA sequences (<500 bases) that represent reverse-transcribed RNA molecules originally transcribed by RNA polymerase III into tRNA, 5S ribosomal RNA, and other small nuclear RNAs. SINEs do not encode a functional reverse transcriptase protein and rely on other mobile elements for transposition. The most common SINEs in primates are called Alu sequences. Alu elements are approximately 350 base pairs long, do not contain any coding sequences, and can be recognized by the restriction enzyme AluI (hence the name).
Insertion-deletion polymorphisms (indels)
a molecular biology term for the insertion or the deletion of bases in the DNA of an organism. It has slightly different definitions between its use in evolutionary studies and its use in germ-line and somatic mutation studies. Types include Minisatellites and Microsatellites
Minisatellites
a class of variable number tandem repeat (VNTR), is a section of DNA that consists of a short series of nucleobases (10–60 base pairs). Minisatellites, which are often simply referred to as VNTRs, occur at more than 1,000 locations in the human genome.
Microsatellites
also known as simple sequence repeats (SSRs) or short tandem repeats (STRs), are repeating sequences of 2-5 base pairs of DNA. It is a type of Variable Number Tandem Repeat (VNTR). Microsatellites are typically co-dominant. They are used as molecular markers in STR analysis, for kinship, population and other studies. They can also be used for studies of gene duplication or deletion, marker assisted selection, and fingerprinting. They often contain di-, tri-, tetra-nucleotide repeats
Single Nucleotide Polymorphisms (SNPs)
a DNA sequence variation occurring commonly within a population (e.g. 1%) in which a single nucleotide — A, T, C or G — in the genome (or other shared sequence) differs between members of a biological species or paired chromosomes. The frequency is about 1 in ~1000 bp and are PCR-detectable markers, easy to score, widely distributed
Copy number variations (CNVs)
a form of structural variation—are alterations of the DNA of a genome that results in the cell having an abnormal or, for certain genes, a normal variation in the number of copies of one or more sections of the DNA. CNVs correspond to relatively large regions of the genome that have been deleted (fewer than the normal number) or duplicated (more than the normal number) on certain chromosomes. The variation in segments of genome can range from 200 bp – 2 Mb and can range from one additional copy to many. They can be array comparative genomic hybridization (array CGH). CNV loci may cover 12% of genome. Implicated in increasingly larger number of diseases. Some CNV regions involved in rapid & recent evolutionary change. Such regions are often enriched for human specific gene duplications, enriched for genome sequence gaps, enriched for recurrent human diseases. There is a link between evolutionarily adaptive copy number increases and increase in human disease (e.g. 1q21) They play a role of genome architecture
Comparative genomic hybridization
a molecular cytogenetic method for analysing copy number variations (CNVs) relative to ploidy level in the DNA of a test sample compared to a reference sample, without the need for culturing cells. The aim of this technique is to quickly and efficiently compare two genomic DNA samples arising from two sources, which are most often closely related, because it is suspected that they contain differences in terms of either gains or losses of either whole chromosomes or subchromosomal regions (a portion of a whole chromosome). This is achieved through the use of competitive fluorescence in situ hybridization. In short, this involves the isolation of DNA from the two sources to be compared, most commonly a test and reference source, independent labelling of each DNA sample with a different fluorophores (fluorescent molecules) of different colours (usually red and green), denaturation of the DNA so that it is single stranded, and the hybridization of the two resultant samples in a 1:1 ratio to a normal metaphase spread of chromosomes, to which the labelled DNA samples will bind at their locus of origin. Using a fluorescence microscope and computer software, the differentially coloured fluorescent signals are then compared along the length of each chromosome for identification of chromosomal differences between the two sources.
Types of human DNA variation
Types include SNPs, indels, CNVs, and others: chromosomal or larger scale variations, rearrangements, translocations, etc. Variants can be silent (majority) or have a functional effect
gene family
a set of several similar genes, formed by duplication of a single original gene, and generally with similar biochemical functions. Many human genes are members of gene families. Gene family is composed of genes with high sequence similarity (e.g. >85-90%) that may carry out similar but distinct functions. Gene families arise through gene duplication, a major mechanism underlying evolutionary change. Rationale: when a gene duplicates it frees up one copy to vary while the other copy continues to carry out a critical function. It facilitates innovation
Structural Variation
(also genomic structural variation) is the variation in structure of an organism’s chromosome. It consists of many kinds of variation in the genome of one species, and usually includes microscopic and submicroscopic types, such as deletions, duplications, copy-number variants, insertions, inversions and translocations. It is the b roadest sense: all changes in the genome not due to single base-pair substitutions: Copy number variations (CNVs) is the primary type of structural variation. They expose limitations of genome sequencing and genotyping platforms
limitations of genome sequencing
Nextgen DNA sequencing: No mammalian genome has been completely sequenced & assembled. Nextgen sequencing relies on short read sequences. Complex, highly duplicated regions are typically unexamined. Such regions are implicated in numerous diseases, e.g. 1q21. Genome-wide association studies (GWAS): “Missing heritability” for complex diseases: Many large-scale studies implicate loci (e.g. SNPs) that account for only a small fraction of the expected genetic contribution. Many regions of the genomes are unexamined by available “genome-wide” screening technologies: is this where the “missing heritability” lies?
genome-wide association study (GWA study)
an examination of many common genetic variants in different individuals to see if any variant is associated with a trait. GWAS typically focus on associations between single-nucleotide polymorphisms (SNPs) and traits like major diseases. These studies normally compare the DNA of two groups of participants: people with the disease (cases) and similar people without (controls). Each person gives a sample of DNA, from which millions of genetic variants are read using SNP arrays.
Structural chromosomal rearrangements
Chromosomal rearrangements require two DNA double strand breaks (DSBs) and can be induced by a variety of DNA damaging agents. Ionizing radiation directly induces breaks, but numerous other agents that damage DNA produce DSBs during repair. Because DSBs are necessary for meiotic recombination, rearrangements during meiosis are common. Duplications, deletions, inversions, insertions and translocations all appear to have breakpoints in chromosomal regions in which repeated sequences are prevalent. Nuclear protein complexes having both DNA repair and recombination activities share enzymes and associate with chromatin containing repetitive sequences. Structural rearrangements can be inherited and can also lead to further rearrangement during meiosis.Structural rearrangement can also occur with crossing over between repetitive DNA. Two basic types of structural rearrangements exist: balanced and unbalanced
balanced structural rearrangement
Individuals with balanced rearrangements have normal complements of chromosomal material, meaning there is no loss of genetic material. However, these rearrangements have varying stabilities during meiosis and mitosis. Examples of balanced structural rearrangements include the following: inversion, reciprocal translocation, and robertsonian translocation
Inversion
occurs when one chromosome undergoes two double strand breaks of the DNA backbone and the intervening sequence is inverted prior to the rejoining of the broken ends. Paracentric inversions exclude the centromere. Pericentric inversions include the centromere. Chromosomes with inversions can have normal genetic complements, and therefore may produce no phenotypes in carriers of the rearrangement. However, inversions may generate abnormal gametes during meiosis. During the pairing of homologs in meiosis, a loop is introduced in the homolog containing the inversion, which maximizes the association of homologous sequences. If a crossover occurs within the inverted region of a paracentric inversion, both dicentric (two centromeres) chromosomes and acentric chromosomes can be generated, leading to chromosome breakage or loss. In pericentric inversions, crossovers within the inverted region can produce duplications and deletions.
robertsonian translocation
the fusion of two acrocentric chromosomes within their centromeric regions, resulting in the loss of both short arms (containing rDNA repeats). Robertsonian translocations result in the reduction of chromosome number, but are considered balanced rearrangements because the loss of some rDNA repeats is not deleterious. Carriers of Robertsonian translocations are phenotypically normal, but these rearrangements may lead to unbalanced karyotypes for their offspring, resulting in monosomies and trisomies. Robertsonian translocations involving chromosome 14 are by far the most frequent, constituting ~85% of all Robertsonian translocations. Common examples include a translocation involving chromosomes 14 and 21, karyotype 45,XX, or XY,der(14q;21q), and one involving chromosomes 14 and 13: 45,XY or XY,der(13q;14q). These individuals are trisomic 21 even though they only have 46 chromosomes. Note that some abbreviates a Robertsonian translocation as “rob”, but this is often simplified to “der” to indicate a chromosome derivative. There is no contribution with maternal age related to this mode of downs syndrome
reciprical translocation
results from the breakage and rejoining of non-homologous chromosomes, with a reciprocal exchange of the broken segments. As with inversions, carriers of reciprocal translocations have an increased risk of producing unbalanced gametes; balanced translocations are often found in couples that have had two or more spontaneous abortions, and also in infertile males. When the chromosomes of a carrier of a balanced reciprocal translocation pair at meiosis, a quadrivalent figure is formed. At anaphase, these chromosomes are segregated in one of three ways, referred to as alternate, adjacent-1, and adjacent-2 segregation.
46,XX,inv(9)(p13q13)
a female with an inversion of the sequences between band 13 on the short arm and band 13 on the long arm of chromosome 9.
46,XX,t(9;22)(q34;q11.2)
a female with a translocation involving chromosomes 9 and 22, which has been shown to cause chronic myelogenous leukemia.
alternate segregation
the most frequent meiotic segregation pattern, produces gametes that have either the normal chromosome complement or two reciprocal translocation chromosomes, both of which are balanced with respect to chromosome complement. Most likely normal. This mode of seperation is preferred over adjacent 1 and 2
adjacent-1 or 2 segregation
Results from pairing in meiosis 1 as quadrivalent complex. If you have 2 normal nonhomologous chrom A and B and their transloc forms a and b. During meosis, you get 1 off each nonhomologous in a cell (normal chrom+transl chrom Ab or aB). In adjacent 1, homologous cenromeres go to seperate daughter cells (as is normally the case in meiosis I), whereas in adjacent-2 (which is rare), homologous centromeres pass to the same daughter cell. segregation mechanisms lead to unbalanced gametes. The risks to offspring depend on the specific translocation in question, but the general empirical risk is 5-10% lethality. Division along one of the quadrivalent axis leads to 1, division along the other leads to 2. Such division leads to partial monosomy or trisomy.
Unbalanced structural rearrangement
the chromosome set has additional or missing material. Phenotypes of these individuals are likely to be abnormal. Duplication of genetic material in gametes can lead to partial trisomy after fertilization with a normal gamete, while deletions lead to partial monosomy. Examples of unbalanced chromosomal rearrangements include the following: deletion, duplication, ring chromosome, and isochromosome. If the resulting chromosomes don’t have telomeres, centromeres, and origin of replication, then they will be lost from the population
deletion in chromosome
loss of genetic information that can arise by simple chromosome breakage (two dsDNA breaks) and rejoining, unequal crossing over between misaligned homologous chromosomes or sister chromatids, or by abnormal segregation of a balanced translocation or inversion. Includes terminal deletion and interstitial deletion. The clinical consequences of deletions reflect haploinsufficiency, where the contribution of the remaining normal allele is unable to prevent disease. Moreover, the severity of the phenotype depends on the size of the deletion and the number of genes affected.
46,XY,del(5)(p15)
a deletion of chromosome 5 in the region denoted p one-five. This deletion results in the Cri-du-chat syndrome.
Duplication of chromosome
gain of genetic information, which is generally less harmful than deletion, but can lead to abnormalities (i.e. partial trisomy 21). Duplications can also result from unequal crossing-over or by abnormal segregation during meiosis in a carrier of a translocation or inversion.
Ring Chromosome
a chromosome fragment that circularizes and acquires kinetochore activity for stable transmission to daughter cells (also called a marker chromosome).
kinetochore
the protein structure on chromatids where the spindle fibers attach during cell division to pull sister chromatids apart.
46,XY,r(13)(p11q34)
a male with a supernumary ring chromosome derived from the p11 to q34 region of chromosome 13.
Isochromosome
a chromosome in which one arm is missing and the other duplicated in a mirror-image fashion, possibly occurring through an exchange involving one arm of a chromosome and its homolog at the proximal edge of the arm, adjacent to the centromere. The most common isochromosome observed is an isochromosome of the long arm of the X chromosome, karyotype i(Xq), but it also can occur on autosomes. A small percentage of Down syndrome patients have the 21q21q isochromosome e.g. 46,XX, i(21)(21q21q). Although this is a rare rearrangement, all the gametes of a phenotypically normal carrier of this isochromosome must contain either the 21q21q chromosome (giving 3 copies of chromosome 21 after fertilization), or gametes that lack chromosome 21, resulting in monosomy (inviability) upon fertilization. Thus, 100% of the viable offspring are abnormal.
causes of isochromosome formation
1)misdivision throught the centromerein meiosis II 2) more commonly, the exchange incolcing one arm of a chromosome and its homologue (or sister chromatid) in the region of the arm immediately adjacent to the centromere.
Recurrence risks of chromosomal restructuring
Most chromosome structural abnormalities found in fetuses and newborns that are associated with serious clinical effects are attributable to a random event. They are therefore unlikely to occur again. Moreover, a recurrence can be diagnosed in utero.
genetic counseling with chromosomal structural abnormalities
Occasionally a serious chromosomal abnormality can be inherited from a seemingly normal parent who carries a balanced chromosomal abnormality such as a translocation. In these comparatively rare cases, the recurrence risk could be much increased (e.g. isochromosome 21, where the recurrence risk is 100%!). It is necessary to examine the chromosomes of parents cytologically to exclude the possibility of an inherited abnormality, before counseling patients about recurrence risk.
Contiguous gene syndromes
a clinical phenotype caused by a chromosomal abnormality, such as a deletion or duplication that removes several genes lying in close proximity to one another on the chromosome. The combined phenotype of the patient is a combination of what is seen when any individual has disease causing mutations in any of the individual genes involved in the deletion. While it can be caused by deleted material on a chromosome, it is not, strictly speaking, the same entity as a segmental aneuploidy syndrome. A segmental aneuploidy syndrome is a subtype of CGS that regularly recur,usually due to non-allelic homologous recombination between low copy repeats in the region. Most CGS involve the X chromosome and affected male individuals
Wolf-Hirschhorn syndrome
a condition that affects many parts of the body. Almost everyone with this disorder has distinctive facial features, including a broad, flat nasal bridge and a high forehead. This combination is described as a “Greek warrior helmet” appearance. The eyes are widely spaced and may be protruding. The major features of this disorder include a characteristic facial appearance (facial clefting, prominent ears microcephaly), delayed growth and development, intellectual disability, and seizures. experience delayed growth and development. Intellectual disability ranges from mild to severe in people with Wolf-Hirschhorn syndrome. Wolf-Hirschhorn syndrome is caused by a deletion of genetic material near the end of the short (p) arm of chromosome 4. del(4p16.3)
Beckwith-Wiedemann syndrome
It is classified as an overgrowth syndrome, which means that affected infants are considerably larger than normal (macrosomia) and continue to grow and gain weight at an unusual rate during childhood. Many people with this condition are born with an opening in the wall of the abdomen (an omphalocele) that allows the abdominal organs to protrude through the navel. Other abdominal wall defects, such as a soft out-pouching around the belly-button (an umbilical hernia), are also common. Most infants with Beckwith-Wiedemann syndrome have an abnormally large tongue (macroglossia), which may interfere with breathing, swallowing, and speaking. Other major features of this condition include abnormally large abdominal organs (visceromegaly), creases or pits in the skin near the ears, low blood sugar (hypoglycemia) in infancy, and kidney abnormalities.Children with Beckwith-Wiedemann syndrome are at an increased risk of developing several types of cancerous and noncancerous tumors, particularly a rare form of kidney cancer called Wilms tumor, a cancer of muscle tissue called rhabdomyosarcoma, and a form of liver cancer called hepatoblastoma. The condition usually results from the abnormal regulation of genes in a particular region of chromosome 11. Abnormalities involving genes on chromosome 11 that undergo genomic imprinting are responsible for most cases of Beckwith-Wiedemann syndrome. About 1 percent of all people with Beckwith-Wiedemann syndrome have a chromosomal abnormality such as a rearrangement (translocation) or abnormal copying (duplication) of genetic material from chromosome 11.
genomic imprinting
an epigenetic phenomenon by which certain genes can be expressed in a parent-of-origin-specific manner. Both maternal and paternal alleles of autosomal genes are typically expressed. However, approximately 100 autosomal genes in the mammalian genome are inherited in a silenced state from one of the two parents, and in a transcriptionally active state from the other, thereby rendering the individual functionally hemizygous for these genes. This process has been referred to as parental imprinting, genetic imprinting, or gametic imprinting, and represents an important epigenetic mechanism of inheritance. Imprinting takes place during gametogenesis, before fertilization. after concenption, the imprint controls gene expression within the imprinted region. It is reversible because a female must be able to convert her paternal inheriented allele in her germline so that she can pass of the maternal imprint to her offspring.
Cri du chat syndrome
del(5p15.2) also known as 5p- (5p minus) syndrome, is a chromosomal condition that results when a piece of chromosome 5 is missing. Infants with this condition often have a high-pitched cry that sounds like that of a cat. The disorder is characterized by intellectual disability and delayed development, small head size (microcephaly), low birth weight, and weak muscle tone (hypotonia) in infancy. Affected individuals also have distinctive facial features, including widely set eyes (hypertelorism), low-set ears, a small jaw, and a rounded face. Some children with cri-du-chat syndrome are born with a heart defect.
Angelman syndrome
del(15q11-q13) (maternal) Characteristic features of this condition include delayed development, intellectual disability, severe speech impairment, and problems with movement and balance (ataxia). Most affected children also have recurrent seizures (epilepsy) and a small head size (microcephaly). Delayed development becomes noticeable by the age of 6 to 12 months. Children with Angelman syndrome typically have a happy, excitable demeanor with frequent smiling, laughter, and hand-flapping movements. Hyperactivity, a short attention span, and a fascination with water are common. Most affected children also have difficulty sleeping and need less sleep than usual.The 15q11-q13 region contains three paternally expressed genes. Although no maternally expressed genes have so far been identified in this cluster, one is predicted to exist based on the fact that the inherited form of Angelman syndrome is exclusively inherited from mothers. These patients have a deletion of approximately the same region of chromosome 15 in prader willi syndrom, but on the maternally derived homolog. In this case, the information contained on the normal paternally derived chromosome 15 is inactivated due to DNA methylation. These defects effect the expression of UBE3A, which encodes a ubiquitin ligase involved in early brain development. 70% occur from deltion of maternal gene, followed by methylation of paternal alle. less than 5% occur from uniparental paternal disomy (nondisjuction is less common in males).
Williams syndrome
This condition is characterized by mild to moderate intellectual disability or learning problems, unique personality characteristics, distinctive facial features, and heart and blood vessel (cardiovascular) problems. Williams syndrome is caused by the deletion of paternal genetic material from a specific region of chromosome 7. del(7q11.2), followed by methylation of the maternal copy (%70). 25% of cases result from uniparental disomy followed by methylation of both copies of the AS gene It is currently thought to arise due to defects in SNORD116 snoRNA genes (non-coding RNAs typically involved in guiding modifications of other RNAs). In PWS, these small nucleolar RNAs may be involved in mRNA modification, possibly by modulating alternative splicing. The region of this gene is flanked by multiple repetitive elements, therefore deletion in this region is common
Prader-Willi syndrome
In infancy, this condition is characterized by weak muscle tone (hypotonia), feeding difficulties, poor growth, and delayed development. Beginning in childhood, affected individuals develop an insatiable appetite, which leads to chronic overeating (hyperphagia) and obesity. Some people with Prader-Willi syndrome, particularly those with obesity, also develop type 2 diabetes mellitus (the most common form of diabetes). People with Prader-Willi syndrome typically have mild to moderate intellectual impairment and learning disabilities. Behavioral problems are common, including temper outbursts, stubbornness, and compulsive behavior such as picking at the skin. Prader-Willi syndrome is caused by the loss of function of genes in a particular region of chromosome 15. In 70% of patients, the syndrome is the result of a cytogenetically observable deletion involving the long arm of chromosome 15 (15q11-q13), occurring on the chromosome 15 homolog inherited from the patient’s father. These patients have a normal, maternally derived homolog of chromosome 15. However, this region on the maternally derived chromosome is methylated, and transcriptionally silenced. del(15q11-q13)
Langer-Giedion syndrome
People with this condition have multiple noncancerous (benign) bone tumors called exostoses. Multiple exostoses may result in pain, limited range of joint movement, and pressure on nerves, blood vessels, the spinal cord, and tissues surrounding the exostoses. Affected individuals also have short stature and cone-shaped ends of the long bones (epiphyses). The characteristic appearance of individuals with Langer-Giedion syndrome includes sparse scalp hair, a rounded nose, a long flat area between the nose and the upper lip (philtrum), and a thin upper lip. Affected individuals may have some intellectual disability. It is caused by the deletion or mutation of at least two genes on chromosome 8. del(8q24.1) Also called Tricho-rhino-pharangeal syndrome
Miller-Dieker syndrome
a condition characterized by a pattern of abnormal brain development known as lissencephaly. Normally the exterior of the brain (cerebral cortex) is multi-layered with folds and grooves. People with lissencephaly have an abnormally smooth brain with fewer folds and grooves. These brain malformations cause severe intellectual disability, developmental delay, seizures, abnormal muscle stiffness (spasticity), weak muscle tone (hypotonia), and feeding difficulties. Seizures usually begin before six months of age, and some occur from birth. They also tend to have distinctive facial features that include a prominent forehead; a sunken appearance in the middle of the face (midface hypoplasia); a small, upturned nose; low-set and abnormally shaped ears; a small jaw; and a thick upper lip. It is caused by a deletion of genetic material near the end of the short (p) arm of chromosome 17. del(17p13.3)
WAGR syndrome
Wilms tumor, aniridia (an absence of the colored part of the eye (the iris)), genitourinary anomalies, and mental retardation. WAGR syndrome is caused by a deletion of genetic material on the short (p) arm of chromosome 11. del(11p13)
DiGeorge syndrome
Medical problems commonly associated with DiGeorge syndrome include heart defects, poor immune system function, a cleft palate, complications related to low levels of calcium in the blood, and delayed development with behavioral and emotional problems. is a disorder caused by a defect in chromosome 22. del(22q11.2)
Velo-Cardio-Facial syndrome
characterized by medical problems include: cleft palate, or an opening in the roof of the mouth, and other differences in the palate; heart defects; problems fighting infection; low calcium levels; differences in the way the kidneys are formed or work; a characteristic facial appearance; learning problems; and speech and feeding problems. VCFS is also called the 22q11.2 deletion syndrome
