Learning Objectives Week 1 Flashcards
Mendels First Law
Law of Segregation
alleles separate in meiosis such that each gamete (egg/sperm) receives one copy from each allele pair. (Half from mom, half from dad)
Mendels Second Law
Law of Independent Assortment
segregation of each pair is independent from other alleles at other loci
X-linked (Recessive) inheritance
- No male to male inheritance
- Affected males: all daughters are carriers
- Carrier females: 1/2 sons affected, 1/2 daughters carriers
Autosomal Dominant
- (Vertical) does not skip generations
- affects males and females equally
- there IS male to male transmission
- can be sex specific (ex. prostate cancer)
Autosomal Recessive
- (Horizontal)
- one generation affected
- Consanguinity increases chances
- carriers do not have the phenotype
Inheritance Pattern in Single-Gene Disorders
(2 Factors)
-Quality of Phenotype
(Dominant vs. Recessive)
Dominant phenotype is expressed in heterozygote state ( one mutant allele can cause disease)
Recessive phenotype only seen in homozygotes
Inheritance Pattern in Single-Gene Disorders
(2 Factors)
-Location of Gene Locus
(Autosomal vs Sex Chromosome)
-chromosomal location of gene locus can be on autosome (1-22) or on sex chromosome (X or Y, probably X)
X-linked (Dominant) inheritance
- No dad to son transmission
- but 100% of daughters will get it from dad. -50% of sons will get the trait if mom has it.
- pretty rare but if dad has it than all daughters will have it as well
List Threats to Mendelian Inheritance
three things
PEP
Penetrance
Expressivity
Pleiotropy
Threats to Mendelian Inheritance
Penetrance
Think of the light swtich analogy, is it on or off?
In other words if you have the mutation are you affected by it (light on) or not affected (light off). Can have incomplete penetrance and can be age dependent.
Threats to Mendelian Inheritance
Expressivity
The light dimmer. The light is on but how “bright” is it. In other words what is the severity of the expressed phenotype. Can be affected by sex, environment, modifier genes (outside of traits genetic locus), stochastic/random effects, and phenocopies (same phenotype due to non-genetic factors)
Threats to Mendelian Inheritance
Pleiotropy
“What does the light switch control and turn on or off”
Polysystemic will cause many different phenotypic expressions in different organ systems (Ex. neurofibromatosis type I).
Monosystemic, just affects one thing specifically, not as complex.
Human Genome Organization
Genome) & (Phenotype
Genome is a record of evolutionary history, reflects different selection pressures and adaptive genomes that were retained.
Genotype + environment = selects for phenotype.
3x10^9 bp = haploid human genome, distributed on 46 chromosomes (23 pairs, 22 autosomes, 1 pair of sex chromosomes
Human Genome Organization
Random Genomic Variation
Random Genomic Variation is the fuel of evolution. Variation can have mostly deleterious affects, but some are advantages and leads to adaptation. Genetic disease is a byproduct of evolution. Roughly 30 new mutations per individual.
Human Genome Organization
Dynamic and Non-Random
Shuffling of regions at each meiosis due to recombination. Can produce somatic DNA changes as well as germ-line DNA changes.
Human Genome Organization
Frequency of SNP
There is no “one human genome” there are many. Single nucleotide polymorphisms average 1 SNP every 1000 bp between any two randomly chosen human genomes. 99.9% identical and yet 3 million differences
Human Genome Organization
List DNA Variation Types
- Insertion-deletion polymorphisms (indels)
- Single Nucleotide Polymorphisms (SNPs)
- Copy Number Variations (CNVs)
- OTHER
Human Genome Organization
(DNA Variation Types)
-indels
(indels)
-Minisatellites: tandemly repeated 10-100 bp blocks of DNA; VNTR (variable number of tandem repeats)
-Microsatellites:
di, tri, tetra-nucleotide repeats; greater than 5x10^4 per genome; STRPs (short tandem repeat polymorphisms)
Human Genome Organization
(DNA Variation Types)
-SNPs
SNPs:
- frequency of 1 in 1000bps;
- PCR detectable markers, easy to score, widely distributed
Human Genome Organization
(DNA Variation Types)
-CNVs
CNVs:
- variation in segments of genome from 200bp-2Mb
- can range from one additional copy to many
- array comparative genomic hybridization (array CGH)
Human Genome Organization
(DNA Variation Types)
-OTHERS
OTHERS:
chromosomal or larger scale variations, rearrangements, translocations; variants can also be silent (majority) or have a functional effect
Ex) extra DUF1220 is macrocephaly, autism; deletions is microcephaly and schizophrenia
Human Genome Organization
Components
- Gene Rich: Chr 19
- Gene Poor: Chr 13, 18, 21
- Stable: majority of genome
- Unstable: dynamic regions; many disease associated ( SMA Chr5q13; Digeorge Syndrome Ch22q; 12 diseases 1q21)
Human Genome Organization
euchromatic & heterochromatic
Euchromatic:
more relaxed, ( genes)genome sequencing focus, there is no completely sequenced & assembled genome; many gaps still remain in eukaryotic regions
Heterochromatic:
generally un-sequenced
Human Genome Organization
(Genomic DNA Sequence Category and Frequency
1.5% of genome is protein-coding/translation (directly coding).
20-25% of genome represented by genes (exons, introns, flanking regulatory sequences involved in gene expression).
50% “single-copy” sequences (one copy of a gene).
40-50% of genome is classes of “repetitive DNA” that get repeated many many times.
Human Genome Organization
(Repetitive DNAs - type, location, frequency)
-Tandem Repeats
Tandem Repeats (satellite DNAs)
- Not clustered locally, some are in different parts of genome (used as basis for cytogenetic binding)
- Can be found in heterochromatic regions on long arms of Chr 1, 9, 16 and Y ( these are hotspots for human-specific evolutionary changes)
- “alpha-satellite” repeats (171 bp repeat unit) found near centromeres of all human chromosomes (suggested role in chromosome segregation)
Human Genome Organization
(Repetitive DNAs - type, location, frequency)
-Dispersed Repeats
-Alu family (ex. of Short Interspersed Repetitive Elements –> 300 bp related members and 500,000 copies in genome)
-L1 family (ex. of Long Interspersed Repetitive Elements –> 6kb releated members and 100,000 copies in genome
*Alu’s and L1’s can be medically relevant because retrotransposition of the copy in the middle of another gene may inactivate that gene, or activate them.
-repeats may facilitate bad recombination events between different copies of dispersed repeats leading to disease –> NAHR, non-allelic homologus recombination
NAHR is a form of homologous recombination that occurs between 2 chunks of DNA that have high sequence similarity, but are not alleles. When NAHR occurs between these DNA chunks, can get more deletions or duplication.
Human Genome Organization
Number and Type of Human Genes
25,000-30,000 genes comprised of protein-encoding genes, RNA-encoding genes, and pseudogenes (non-functional, homologous copies of existing genes; can be “intron-containing or intronless”.
Human Genome Organization
Gene Families
Gene Families
Genes with high sequence similarity (85-90%) that have similar but distinct functions (some clustered, some dispersed)
( they duplicate, so have copies that may be better, old ones there to still carry the load * look at(Gene Duplication Evolutionary Mechanism)card )
Human Genome Organization
Gene Duplication Evolutionary Mechanism
Gene families arise through gene duplication. This is a major mechanism underlying evolutionary change because when a gene duplicates, it frees up one copy to vary, while the other copy carries out the critical function. Allows for innovation.
Human Genome Organization
Potential Disease Side Effects
You can have multiple copies of a gene which can give you extra capabilities, but at the same time put you at risk for disease because you have all these increases in gene copy number (DUF1220).
Human Genome Organization
“Missing Heritability” Problem
“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?
Missing Heritabilty problem, explains that simple mendelian genetics doesnt explain everything, genetic issues in heterochromatin with CNVS and we cant analyze them.
Human Genome Organization
Sequencing limitations
Better sequencing needed, because we need more insight into these CNV regions ( because they are so long and full of repeats that with normal sequencing, they are full of giberish)
Next gen sequencing, uses short read sequences and the complex highly duplicated regions go unexamined ( which is bad because they can be disease-linked). (ex. 1q21)
Human Genome Organization
Structural Variation
• Broadest sense: all changes in the genome not due to single base-pair substitutions:
• Copy number variations (CNVs)
– Primary type of structural variation
– 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
- 1q21.1; 9p13.3-9q21.12, 5q13.3
- Link between evolutionarily adaptive copy number increases and increase in human disease (e.g. 1q21)
- Role of genome architecture
Numerical Chromosomal Anomalies
How meiosis produces genetic variability among offspring
In meiosis, you get recombination during which homologous cross over occurs ( again remember this is not between sister chromatids, which is why you end up with 4 diff haploid products). In particular meiotic prophase 1 is critical during meiosis. Maternal and paternal homologous of each chromosome become paried 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 occuring at this stage generate physical links between homologous. These crossovers are known as “chiasmata”. On average 2-3 crossovers occur on each chromosome resulting in genetic re-assortment. In short, random shuffling of genetic material due to crossover events, resulting in a vast increase in genetic variability.
Numerical Chromosomal Anomalies
Mitosis Info, try comparing to meiosis
Mitosis
A. one round of chromosome segregation, resulting in two 2n daughter cells identical in chromosomal content to the parental cell
B. DNA replication precedes each round of chromosome segregation
C. NO pairing of homologous chromosomes
D. infrequent recombination
E. centromeres on paired sister chromatids segregate at each anaphase
F. occurs in somatic cells and in germ line precursor cells prior to entry into meiosis
Numerical Chromosomal Anomalies
Meiosis Info, try comparing to mitosis
A. two rounds of chromosome segregation without an intervening round of DNA replication
B. parental cells must be diploid and the chromosome number is halved in the resultant cells
C. requires the pairing of homologous chromosomes and recombination for its successful completion
D. centromeres on paired sister chromatids divide only at anaphase II in a normal meiosis
E. occurs only in the germ line
Numerical Chromosomal Anomalies
Nondisjunction in Meiosis I
In normal meiotic recombination, you get four, genetically variable haploid cells.
If you have nondisjunction in meiosis I, your homologous pairs don’t split properly in the first division, so you end up with one 4N cell and one 0N cell (as opposed to two 2N cells) –> your resulting gametes will be 100% abnormal (two 2N [or N+1] cells, and two 0N cells [or N-1]). –>two diploid cells, two non-genetic cells.
Numerical Chromosomal Anomalies
Nondisjunction in Meiosis II
In normal meiotic recombination, you get four, genetically variable haploid cells.
If you have nondisjunction in meiosis II, the homologs separate fine, but the sister chromatids do not. So you get two, normal haploid cells, one 2N cell, and one 0N cell 50% abnormal gametes.
Numerical Chromosomal Anomalies
Chromosome Identification and Nomenclature
Chromosomes have been classified historically on the basis of several characteristics. p= short arm; q= long arm. A major determinant in this classification system is the relative position of the centromere (primary constriction) on the chromosome. On this basis, human chromosomes are divided into three categories:
- 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.
Numerical Chromosomal Anomalies
Visualizing chromosome structure
Chromosomes are also classified cytogenetically based on banding patterns observed microscopically after treatment with stains such as Giemsa, quinocrine, DAPI (4’,6-diamino-2-phenylindole), Hoechts, etc. These patterns result from the differential staining of various chromosomal regions (e.g. regions with high G+C, or A+T base compositions, or the presence of heterochromatin) with the dyes listed above. The banding pattern is unique to each human chromosome and allows the unequivocal identification of each chromosome. Primarily we visualize karyotype via G-stain in which we isolate pt’s lymphocytes during metaphase and stain the chromosomal proteins (high GC-content stains lighter) use banding patterns to identify chromosomes. There are other ways to visualize
Numerical Chromosomal Anomalies
International Nomenclature
The classification of human chromosomes is decided and updated by the Standing Committee of Human Cytogenetic Nomenclature and reported as the International System for Human Cytogenetic Nomenclature (ISCN). Short arm locations are labeled p (petite) and long arms are labeled q. 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.
Numerical Chromosomal Anomalies
Polyploidy, Aneuploidy and Maternal Age Effect
Polyploidy = extra copies of all chromosomes (3n, 4n) generally caused by 1 egg fertilized by 2 sperm. Aneuploidy = loss or gain of certain chromosomes (trisomy 21, monosomy X) generally due to nondisjunction events involving frequency/location of recombination in Meiosis I. Maternal age also a contributing factor.
-Maternal age effect = perhaps when women age, their cellular machinery gets worse at dealing with bad recombination events (1st hit = bad recombination event, 2nd hit = bad machinery). Terminalization = loss of cohesion between sister chromatids = movement of chiasmata towards ends of homolog pairs –>precocious separation of homologous chromosomes and nondisjunction.
Numerical Chromosomal Anomalies
Trisomy 21
Trisomy 21 – Down syndrome Characteristic facies, short stature, hypotonia, moderate intellectual disabilities Congenital malformations – endocardial cushion defects, duodenal atresia (closing off or narrrowing) and other gastrointestinal anomalies, Hirschprung disease(large intestine disease, makes it hard to poop, loss motility or peristalstic movements). 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.
Numerical Chromosomal Anomalies
Trisomy 18
Trisomy 18 – Edwards syndrome
Intrauterine growth retardation, characteristic facies, severe intellectual disabilities, characteristic hand positioning.
Congenital malformations – valvular heart disease, posterior fossa CNS maldevelopment, diaphragmatic hernias, renal anomalies
Numerical Chromosomal Anomalies
Trisomy 13
Trisomy 13 – Patau syndrome
Characteristic facies, severe intellectual disabilities
Congenital malformations – holoprosencephaly, facial clefts, polydactyly, renal anomalies
Numerical Chromosomal Anomalies
Klinefelter syndrome
47, XXY – Klinefelter syndrome
Tall stature, hypogonadism, elevated frequency of gynecomastia, high frequency of sterility, language impairment
Numerical Chromosomal Anomalies
Turner syndrome
45, X -Turner syndrome
Short stature, webbed neck, edema of hands and feet, broad shield-like chest, narrow hips, renal and cardiovascular anomalies, gonadal dysgenesis (failure of ovarian maintenance).
Structural Chromosomal Anomalies
Mechanism of common chromosomal rearrangements
Balanced and unbalanced rearragements.
Chromosomal rearrangements require two DNA double strand breaks (DSBs) (fixed by NHEJ) 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 Chromosomal Anomalies
(Balanced Chromosomal Structural Rearrangements)
-Inversion
Inversion:
-INTRAchromosomal rearrangements
-Inverted Segments
-Normal phenotype for carrier in most cases
-familial more common
-de novo is less common
-incidence is 1%
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.
Pericentric inversions:
include the centromere. Break in both the p and q arms. Orient inversions by rotating the inverted segment, holding fast the flanking segments of the chromosome. Think Rec 8 in San Luis Valley.
Paracentric inversions:
exclude the centromere. two breaks within the same chromosome arm.
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.
-Pericentric carrier recombination (with another WT individual) = During meiosis, there’s a drive to align homologous sequences –> can sometimes induce a loop formation to maximize this alignment.
Get 1 normal gene, 1 inverted gene, and 2 genes susceptible to deletion/duplication. Pericentric indicated by p and q in the karyotypic classification.
-Paracentric carrier recombination (with another WT individual).
Get 1 normal gamete, 1 deletion dicentric, 1 deletion acentric, and 1 inversion.
Structural Chromosomal Anomalies
GENERAL: Balanced vs Unbalanced Chromosomal Structural Rearrangements
BALANCED: Individuals with balanced rearrangements have normal complements of chromosomal material, meaning there is no loss or gain of genetic material. There is no phenotypic effect for heterozygote carrier. Exception is when it is at a break point of a gene, disrupts function (rare) However, these rearrangements have varying stabilities during meiosis and mitosis. -inversion -reciprocal translocation -Robertsonian translocation UNBALANCED: 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. -Deletions -Isochromosomes -Duplications -Ring chromosomes
Structural Chromosomal Anomalies
(Balanced Chromosomal Structural Rearrangements)
-Reciprocal translocation
Reciprocal 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. 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. However, adjacent segregation leads to unbalanced gametes.
-If they separate in an ‘alternate’ way –> produce gametes that have either the normal chromosome complement, or 2 reciprocal translocation chromosomes, both of which are balanced.
If they segregate via adjacent-1 or adjacent-2 –> unbalanced gametes who have both partial monosomy and partial trisomy of certain genes.
(Ex: CML happens because of translocation between Chr. 9 and 22–> activated a tumorigenic tyrosine kinase.) Adjacent 1 segregation = homologous centromeres go to different daughter cells. Adjacent 2 = both homologs go to the same daughter cell.
Structural Chromosomal Anomalies
(Balanced Chromosomal Structural Rearrangements)
-Robertsonian Translocation
Robertsonian translocation:
the fusion of two acrocentric chromosomes within their centromeric regions, resulting in the loss of both short arms (containing rDNA repeats such as alpha/beta satellites, satellities I- IV, and rRNA encoding regions). The human acrocentric chromosomes are: 13, 14, 15, 21, 22. Can be homologous or nonhomolgus but both are BALANCED.
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. Increased risk of balanced RT in infertile men. Most common between 13:14 (75% of cases) but can also happen in 14:21 and 21:21; all can be denovo or familial.
Very common between chromosomes 14 and 21. Results in Trisomy 21, but still have 45 chromosomes. During meiosis, chromosomes form a trivalent figure to arrange homologous sequences. Carrier has a normal C21, normal C14, and a Robertsonian translocated 14/21. The alternate segregation pathway can once again produce a normal and a balanced gamete. Alternatively, can get 4 unbalanced gametes (one trisomic 21, and 3 lethal [just 14, just 21, or trisomic 14]). 6 potential gametes, 3 viable ones. In Robertsonian translocation, chromosome count still goes down by 1.
Structural Chromosomal Anomalies
(UNbalanced Chromosomal Structural Rearrangements)
-Deletions
Deletions =
can be terminal (at end of chromosome) or interstitial (in middle). Results from a ds break, with one chunk getting excised out, or unequal crossing over, or from an abnormal segregation. Unless the excised fragment has a centromere and can form a ring, it is not stably transmissible to offspring and you get missing chromosomal information. Results in haploinsufficiency in which normal allele isn’t enough to prevent disease (ex: del(5)(p15) = cri-du-chat).
Structural Chromosomal Anomalies
(UNbalanced Chromosomal Structural Rearrangements)
-Isochromosomes
Isochromosomes =
refers to chromosome in which one arm is missing, so the other arm is duplicated in a mirror-like fashion. Happens either through mis-division through the centromere in meiosis II, OR by exchange between one arm of a chromosome and its homolog at the proximal edge of the arm, adjacent to the centromere. Most commonly involves long arm of X chromosomes, but small % of Down Syndrome pt’s have the 21q21q rearrangement. All gametes will contain the 21q21q chromosome (inherited this from parental carrier who had the isochromosome event) plus Chr. 21 from the WT parent = trisomic. (Still, most trisomy 21 happens due to maternal non-disjunction event).
Structural Chromosomal Anomalies
(UNbalanced Chromosomal Structural Rearrangements)
-Duplications
Duplications =
gain of genetic info; less harmful but can lead to abnormalities (partial trisomy 21)
Structural Chromosomal Anomalies
(UNbalanced Chromosomal Structural Rearrangements)
-Ring chromosomes
Ring chromosomes =
chromosome fragment that circularizes and acquires kinetochore activity stable transmission
