27/03/1431 Dr. Faisal Al-Allaf, fallaf@uqu.edu.sa 1

Dr. Faisal Al-AllafAssistant Professor of Genetics and Molecular Medicine

Umm Al-Qura University Faculty of Medicine, Makkah, Saudi Arabia

fallaf@uqu.edu.saTel/Fax: 5270000 Ext: 4198

The Cellular and Molecular Basis of Inheritance

27/03/1431 Dr. Faisal Al-Allaf, fallaf@uqu.edu.sa 2

لتسهيل فهم المحتوى العلمي والحصول على آامل الدروس لهذا المقرر سيتيح لك التعليم اإللكتروني فرصة . فسيتم تفعيل التعليم اإللكتروني عن بعد

آما سيمكنك من . إجراء اإلمتحانات والمذاآرة واإلسترجاع من البيت بإمكاننا أيضا إجراء الحوارات . الحصول على النسخ االليكترونية للدروس

. حول مواضيع المقرر وبإطالع الجميع

: لتفعيل تسجيلك في التعليم اإلليكتروني عن بعد ، نرجو زيارة الرابط http://el.uqu.edu.sa/jusur/index.php?un_id=uqu

لإلطالع على المعلومات الخاصة بأستاذ هذا المقرر ومعرفة الساعات : المكتبية للتواصل معه ، نرجو زيارة الرابط

http://www.uqu.edu.sa/faallaf

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Course contents (syllabus)GENOME, TRANSCRIPTOME, AND PROTEOME

Cell, DNA and RNAGene structure and genetic codesCell cycle and DNA replication Transcription and post-transcriptional modificationTranslation and post-translational modification

CHROMOSOMES AND CELL DIVISIONChromosomes morphology and classificationCell cycle divisionMitosisMeiosis

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DNA makes RNA makes Protein

Genome is the complete set of genetic instructions in the cell of a particular type of organism including nuclear and mitochondrial DNA

Transcriptome is the entire mRNA content of a cell

Proteome is the collection of functioning proteins synthesized by a living cell

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Composition of the human genome

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Mitochondrial DNAMitochonderial DNA is a circular double-stranded molecule.

It occurs in several copies per mitochonderion and each cell contains thousands of mitochonderia

It accounts for less than 0.0005% of the human genome

Each encoding 37 genes; two rRNAs(16S and 23S), 22 tRNA, and 13 polypeptides involved in oxidative phosphorylation.

The mitochonderia do not have DNA repair enzymes

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Nuclear DNA Intergenic or Extragenic DNA

75% of the human nuclear DNA is extragenic/intergenic (outside or between the genes). Of this 60% is unique to moderately repetitive and 40% is moderately to high repetitive.

Extragenic DNA are predominantly transcriptionally inactive(sometimes described as junk).

The highly repetitive fraction includes microsatellite and minisateliteDNA, which differ in the length of the repeat.

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Nuclear DNA Intergenic or Extragenic DNA

Tandemly repeated DNA sequences can be divided into three groups:Satellite DNA are clustered around the centromere of certain chromosomes. It accounts for approximately 10-15% of the repetitive DNA sequences and consists of very large series of simple or moderately complex, short, tandemly repeated DNA sequences.

Minisatellite DNA consists of two families of tandemly repeated short DNA sequences. These are

Telomeric minisatellite DNAHypervariable minisatellite DNA

Microsatellite DNA consists of tandem single, di, tri, and tetra-nucleotide repeatbase pair sequences located throughout the genome. Microsatellite repeats rarely occur within coding sequences but trinucleotide repeats in or near genes are associated with certain inherited disorders.

Highly repeated interspersed repetitive DNA sequences accounts for approximately one-third of the human genome and are interspersed throughout the genome

Short interspersed nuclear elementsLong interspersed nuclear elements

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Nuclear DNA Gene and gene-related sequence

The coding sequence (exons) represents less than 3% of the nuclear DNA, the reminder having no coding function.

It is estimated that there are up to 25,000 and 30,000 genes (in some books 80,000) in the genome of a diploid cell.

Gene related non-coding sequence includes introns (that interrupt the coding exons), UTR (untranslatedregion), pseudogenes (genes that has been inactivated by mutation or those derived from the mRNA copy of a gene), truncated genes, and gene fragments.

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Nuclear DNA Single and multigene families

The gene density are varies between various chromosomes. In addition, the size of genes shows great variability between different chromosomes.

Genes in humans do not usually overlap, being separated from each other by an average of 30kb.

Unique single copy genes: most human genes are unique single copy genes coding for polypeptides which are involved in or carry out a variety of cellular functions. These include enzymes, hormones, receptor and structural and regulatory proteins.

Multigene families can be split into two types: Classical gene families which show a high degree of sequence homology.Gene super-families which have limited sequence homology but are functionally related.

Heterochromatic and centromeric regions are mostly non-coding, with the highest gene density observed in sub-telomeric regions.

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Genes are coded massages written into an enormously long molecule called DNA

Gene is the unit of inheritance

Genes are made up of DNA and contain instructions for making a specific protein

DNA can copy itself and the synthesis of new DNA is called replication. DNA synthesis occur in the nucleus

DNA can also serves as a template for making RNA, the process of synthesis of new RNA from DNA is called transcription. RNA synthesis occur in the nucleus

Translation is the synthesis of polypeptide molecules or protein from the corresponding mRNA transcript. Translation occur in the cytoplasm

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Structure of eukaryotic gene

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ORGANISATION OF GENESThe open reading frame: a sequence with variable length that dose not contain stop codons and therefore can be translated. The sequence beginning with start codon (ATG) which exist at the 5' end of genes.

TATA boxes: These regions are about 20-30 bases to the 5' end (left) of the open reading frame (ATG). TATA boxes direct important enzymes to the correct initiation site for transcription.

Exons: are the functional portions of gene sequences that code for proteins.

Introns: are the non-coding sequences which separate the coding sequence (exons).

Termination codon: the end of translation is signified by a termination codon at the 3' end of genes. The termination codon could be TAA, TAG, or TGA.

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The promoters for genes that code for tissue specific (luxury) proteins include a ‘TATA box’ with a sequence that is a variant of 5’-TATAAA-3’ at about 25 bpupstream of the transcription initiation site. Genes that code for housekeeping proteins instead usually have one or more ‘GC boxes’ in variable positions, containing a variant of 5’-GGGCGG-3’. Another common promoter element is the ‘CAAT box’.

Transcription factors are proteins that bind to promoter sequences and initiate transcription. Typically they contain an active domain and a DNA binding domain. The DNA binding domains are of four types: the leucin zipper, the helix-loop-helix, the helix turn helix and the zinc finger.

Structure of eukaryotic gene

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How can 4 bases code for 20 amino acids?

1. How many bases make up a codon?2. Do codons overlap?3. Are there gaps in the code?4. What are the code words?

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Unit of information is the codonDNA is composed of four different nitrogenous bases, then a single base cannot specify one amino acid.

If two bases were to specify one amino acid, there would only be 42 or 16 possible combinations.

If three bases specified one amino acid then there would be would be 43

or 64. This is more than enough to account for all the 20 known amino acids and is known as the genetic code.

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Codon: trinucleotide in mRNA codes for a specific amino acid or a stop-start signal

Some amino acids are coded for by more than one triplet.

Termination of translation of the mRNA is signaled by the presence of one of the three stop or termination codons (UAA, UGA and UAG)

No overlap, read sequentially in 5’ - 3’ direction

DNA 5’ - AGTATGCAGTCAAGTCAGTCATCAAGTCAGTAATCAGTC- 3’RNA 5’ - AGUAUGCAGUCAAGUCAGUCAUCAAGUCAGUAAUCAGUC- 3’

Direction of reading

Genetic code

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References and Private ReadingThese slides are only a handout and the students must read the text book

(Emery’s element of medical genetics)

1. Emery’s Elements of Medical Genetics, 13th edition 2007, by Peter TURNPENNY and Sian ELLARD. Churchill Livingstone ELSEVIER. ISBN: 978-0-7020-2917-2

2. Medical Genetics at a Glance, 2nd edition 2008, by Dorian PRITCHARD and Bruce KORF. Blackwell Publishing. ISBN: 978-1-4051-4846-7

3. Genetics for Dummies, 2005, by Tara Robinson, Wiley Publishing, Inc. ISBN: 978-0-7645-9554-7

4. Cell Biology and Genetics, Crash Course, 2nd edition 2006, by Manson, Jones, Morris, Michael STEEL and Dan HORTON-SZAR. MOSBY ELSEVIER. ISBN: 0-7234-3248-1

5. Human Molecular Genetics, 3rd edition, 2003, by STRACHAN T. and A. READ. Garland science/Taylor and Francis group. ISBN: 978-0-8153- 4182-6

6. Genomes, 3rd edition 2006, by T.A. BROWN. Garland science, ISBN: 978-0-8153-4138-3

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AcknowledgmentsFor the providers of all the educational materials (video clips, pictures, diagrams and charts) including publishers, pharmaceutical companies or unknown internet users who made their material available for use, in this and other presentations, I offer heartfelt thanks and deep appreciation.

I feel particularly grateful to faculty, staff, and our brilliant students who provided a unique intellectual and wonderful environment for work.