human genetics

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•What is human genetics?

•The Central Dogma of molecular biology and genetics

•DNA to the chromosome

•Mutation (base level & chromosome level)

•Genetics and inheritance

2 Human genetics, Faculty of Medicine Brawijaya University

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Human genetics is the study of the human genes

Study of the genes and they role in: Cells organismpopulation

Genes is DNA segments that have a functional role in the cell and are responsible for inheritance of traits (gametes)


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DNA carries the genetic information of a cell and consists of thousands of genes which serves as a recipe on how to build a protein molecule Proteins perform important tasks for the cell functions it could be autocrine, paracrine, endocrine system.

Glossary: DNA replication; transcription; translation


Gene activity can be turned on and off at the level of transcription by protein factors interaction with promoter that can prevent or allow transcription (e.g. transcription factor)

Protein factor present in a certain type of cells Human pancreatic cells

insulin Progenitor RBC

hemoglobin Although, progenitor RBC

embryo embryonic hemoglobin


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Keywords:

Zygote differentiated cells human Gamete cells, meiosis

Somatic cells, mitosis

Haploid (n, 23 chromosomes)

Diploid (2n, 46 chromosomes)

Note:

Undifferentiated cells pluripotent stem cells


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Oktamer histone

Spacer DNA plus H1 histone

Sister chromatid



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Cytogenetics: the study of chromosome and cell division

Chromosome can be seen clearly during metaphase, maximally condensed


Chromosome banding staining (Giemsa) for identification and detection if any abnormality >4Mbp

The light bands on chromosome regions rich in GC and genes.

Dark bands rich in AT and few on genes. Ex: Chromosome 19, dense with genes, has few dark bands.

Metaphase spread

Idiogram

Fig. normal male karyotyping12

46,XY

Human genetics, Faculty of Medicine Brawijaya University

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Telocentric

Absence in human

Some authors denotes extreme acrocentric chr in human as telocentric, such as: 21, 22, Y

Acrocentric: 13, 14, 15, 21, 22

Submetacentric

Metacentric

p/shortarm

q/longarm

Chromatid; double = sister chromatid


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Is a change in the genetic material

Can occur in non-coding or coding sequences Mutation in promoter regions harmful

Somatic cells is not transmitted to offspring (≠ germinal cells)

Can occur in base level and chromosome level

Base level mutation, example: Wild type: (DNA) … AAA CUC CAC UUC UUC …

(protein) … phe glu val lys lys

Mutant … AAA CUC C ACU UCU UC… (deletion frameshift)

… phe glu (stop) xxx xx premature termination truncated protein


Class Group Type Effect on protein product

Stable/fixed

Synonymous Substitution Silent mutation/same aa no effect

Non-synonymous

Substitution- Missense

- Nonsense

Diff aa:Chemically diff ≠ chemically similar (no effect)Stop codonloss of function/activity/stability

Deletion/insertion

Frameshift/premature termination

Dynamic/unstable

Triple repeat Expansion Altered gene expression/transcription The repeat will be increase in next generation, ex: fragile X, Huntington disease, myotonic dystrophy


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Abnormalities of chromosome:

1. Numerical (~heteroploid):

Polyploidy: addition one or more complete haploid chr. (n) Triploidy (3n); tetraploidy (4n)

Aneuploidy: loss or gain of one or more chromosomes, the most common mechanism is in meiotic nondisjunction (during M1/M2, usually during M1)Monosomy (lethal in autosomal chr.), exception monosomy X

chromosome (Turner syndrome, 45,x); Trisomy:

Trisomy:

Autosomal chr.: trisomy 13, trisomy 18, trisomy 21.

Sex chr.: klinefelter syndrome (47,xxy), xyy syndrome (47,xyy), trisomy X (47,xxx)

2. Structural17 Human genetics, Faculty of Medicine Brawijaya University

Nondisjunction is failure of homologous chr or sister chromatids to separate during formation of daughter cells.

ND could happened during meiosis or mitosis.

Mitotic nondisjunctiongives consequences mosaicism


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Occur during mitosis after conception

Earlier more severe


If parent(s) has:

Somatic mosaicism not inherited

Gonadal/germline mosaicism could be inherited


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The most common chromosomal aneuploidy

An extra genetic material from chromosome 21 results from:

1. ~95%: Nondisjunction of chromosome 21 during meiosis (classic trisomy/nonfamilial; recurrence risk is <1%) because of maternal (~95%) and paternal (~5%) origin due to:

Aging of ova in meiosis I

Delayed fertilization cause aging of ova in meiosis II

Aging of sperm

2. ~4%: Unbalanced translocation

3. ~1%: mosaicism , the person who has 2 cell lines, 1 normal and 1 with trisomy 21 due to mitotic nondisjunction.



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45,X

Turner syndrome


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Triploidy (3n)

Miscarriage tissue

remnant

69,XXY



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1. Translocations

Reciprocal

Robertsonian

2. Deletion

3. Insertion

4. Invertion Pericentric

Paracentric

5. Ring chromosome

6. Isochromosome


Reciprocal: involves breakage of at

least 2 chromosomes with exchange of the fragments; common in chr. 11 and 22

Chromosomes involved in the translocations cannot pair normally with their homolog to form bivalent during M1 (profase) then form a cluster called pachytenequadrivalent


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Robertsonian

Results from breakage of two acrocentricchromosomes (13,14,15,21,22) at or close to their centromeres with subsequent fusion of their long arms (the short arms/satellite of each chromosome are lost).

Total chromosomes number is reduced to 45.

Common in chromosomes 13 and 14.


Deletions The loss of part of a

chromosome and results in monosomy for that segment of the chromosomes.

Insertions A segment of one

chromosome becomes inserted into another chromosome.

Duplication

Ring chromosome

Isochromosome


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True of false:

1. Normally, a person has 46 chr in his/her karyotype.

2. Nondisjunction can occur during meiosis I or II.

3. During MI chromatids separate and during MII the members of homologous pair separate.

4. Half of your chr were inherited from your father and half were inherited from your mother.

5. Somatic mutation will transmit to the offspring.

Fill the blanks:

1. If the parental cell has 24 chr, the daughter cells following meiosis will have….chr.

2. Post-fertilization mutation will result….


True of false:

1. Normally, a person has 46 chr in his/her karyotype. (T)

2. Nondisjunction can occur during meiosis I or II. (T)

3. During MI chromatids separate and during MII the members of homologous pair separate. (F)

4. Half of your chr were inherited from your father and half were inherited from your mother. (T)

5. Somatic mutation will transmit to the offspring. (F)

Fill the blanks:

1. If the parental cell has 24 chr, the daughter cells following meiosis will have….chr. (12)

2. Post-fertilization mutation will result…. (mosaicism)


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Classical patterns:

Dominant Recessive

Autosome Autosomal dominant:- males ~ females- both sexes could be affected- could be found in every generation- male to male transmission

Autosomal recessive:-Males ~ females- both parents are carriers- Increased incidence of parental consanguinity

Sex chromosome (e.g. chr X)

X-linked dominant:- ~ X-linked recessive due to X inactivation (mutant allele is expressed in only a proportion of cells)

X-linked recessive:-Males affected almost exclusively- transmission through carrier female- no male to male transmission- all daughters of affected males are carriers


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Dominant

Recessive


One traits is governed by two or more sets of alleles, possibly located on many different pairs of chr.

The more genes involved more variation phenotypes.

Skin color; body heights


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When the traits is controlled by multiple allele.

Blood types is controlled by 3 alleles (A, B, none/O)

Codominant


1. What is the darkest child that could result from a mating between light and very light individual?

2. What is the lightest child that could result from a mating between two medium-brown individuals?

3. Determine which baby belongs to which parents:

baby 1, type O; baby 2, type B

Mrs Ahmad, type A; Mr Ahmad, type A

Mrs Doni, type A; Mr Doni, type AB


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What is the darkest child that could result from a mating between light and very light individual? Light

What is the lightest child that could result from a mating between two medium-brown individuals? Very light

Determine which baby belongs to which parents:

baby 1, type O; baby 2, type B

Mrs Ahmad, type A; Mr Ahmad, type A

Mrs Doni, type A; Mr Doni, type AB



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Documentation of family history.

Record:

names, DOB, appropriate medical record, age of onset of disease, symptoms.

Specific questions related to genetic diseases:

miscarriage, stillbirth, infant death, consanguinity.

I

II

III

IV


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1. A woman is color blind. What are the chances that her sons will be color blind? If she is married to a man with normal vision, what are the chances that her daughters will be color blind? Will be carriers?

2. Both the husband and wife have normal vision. The wife gives birth to a color-blind daughter. What can you deduce about the girl’s parentage?


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1. A woman is color blind. What are the chances that her sons will be color blind? If she is married to a man with normal vision, what are the chances that her daughters will be color blind? Will be carriers?

Answer: 100%; none; 100%

2. Both the husband and wife have normal vision. The wife gives birth to a color-blind daughter. What can you deduce about the girl’s parentage?

Answer: The husband is not the father.


Kingston HM., 2002. ABC Clinical Genetics. BMJ Books, London.

Sadler TW., 2009. Langman’s Medical Embryology 9th

ed.


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human genetics

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