Brian O’Dowd was born in Dublin. He lives in Toronto. O’Dowd is a Professor at the University of Toronto. His novel ‘A Wicklow Girl’, was published in 2017. Available on Amazon etc. Publisher: Tellwell, Canada.
In 2019 he won the prestigious Prix Galien 2019 Canadian Science Award, as reported in the Irish Times. – https://shorturl.at/O94ac
‘Activity in Genes’
By Brian O’Dowd
With my Greatest Respect.
Herein contents limited to a biological determined sex identity only.
For that’s my Bag.
Be gentle.
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Begin. Took breaks from streaming RTE (need more!) and Britbox to peruse science literature, searching for interesting examples of genes being busy ‘occupied’. Took me the ages, yet just drops in buckets. Topics to impress friend over pints, while hearing lots of ‘I don’t think so’ from skeptical guy. Not exhaustive! Michaelangelo took a marble block and carved David, started with loads then removed lots of rubble chips. Oh to have one such pebble crumb today! Inspired by Genius I adopted same policy dealing with divergent opinions. Some still disputed or controversial. Anyways when game is a foot, all fun and games. Have to take sides when seeing fit. Handy things to impress if ‘know it all’. ‘Reading the room’ not to scare people tried avoid jargon. Fear not. Interest for curious, not forgetting equal observant Space aliens. Growing up with Encyclopedia Britanica, now computers these golden ages!
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All humans cut from same cloth with 19,442 genes busy making proteins, while 98% of our DNA does not code for any protein. For sure not junk, that’s profound unsolved mysteries all by lonesome. Today one in 30 babies in USA are twins. If you wondered identical twins share 99.99% of DNA, they say first cousins 12.5% DNA, second cousins 3.12%, third cousins 0.78%. I’m no jack of all trades, more taking horse to water as it were. Each ‘Mention’ to follow serves as direction towards iceberg tip. Still loads to learn as ever.
Cell Division. Human cells dividing requires 600 different genes to pull that off, while bacteria cell division ~ 20 genes involved. Still source of wonder life’s oldest cells became immediately skilled in that art! First there was one cell then two. Howzat again? Unanswered biology ‘motivation’.
Notice.
Nothing else to see here, so just move on.
Sex Chromosomes. “Sex-determining chromosomes” have but two, ‘Y’ makes 61 proteins, ‘X’ with 853 proteins. Females XX one from each parent, males X from mother, Y from father. One female X chromosome once considered to be ‘silent’. Now realised that X activated late in life expressing genes for women benefiting cognitive faculties. That’s advantage! To no surprise men lose Y in some cells with aging: from blood cells 40% at 60 years, 57% at 75. Tell me about it. Loss of Y associated with cancer, mental and heart problems. Even precious Y chromosome size diminishing, Y lost genes 1393 from 1438 over 300 million years. Good news no genes lost since divergence from Rhesus monkey at 2.5 million years. BTW, overall ~15% DNA difference between humans and chimpanzees.
Not simple to compare.
Complicated.
With size of genomes.
Recent discovery length of ‘Y’ varies between individuals, from 45 million to 84 million base pairs. What ramifications I hear you say? Still unknown? Not observed for other chromosomes. Seems females gain more attributes from mother, also women with daughters may live longer, genetic effects? Man’s Y chromosome represents 1% of DNA in each fella’s cell. Tiny tot fighting above it’s weight, used by lads to boss over the world, getting run of themselves at times.
Male Sperm swim faster! ‘Shettles hypothesis’ claimed X heavier than Y allows male sperm swim faster towards target egg. From that mixed bag males getting head of themselves racing females. Obviously neither side winning all the time.
‘Boy sperm’ faster being lighter.
X being 3 times longer than Y.
Up shot creates more males.
Now 4.17 billion men, 4.13 billion women.
Narrow margins.
I’m a garsun by just that much!
See!
BTW male eunuchs have longer lives.
Women live longer. By 7 years, using maths clocks in at 12%. Worn down male age 76.5 years and more sprightly female 81.4 years. Women’s ‘double XX’ gamble, one gene fails they’ve spare on hand! Like NASA with back up, while men keep ‘fingers crossed’. Other mammals exhibit same female advantage.
Mother’s Retain Baby DNA. Having babies makes changes! Baby cells enter Mother’s blood stream, remain happily situated in various organs for decades. Called Fetal Microchimerism! Remember men also contributed to ‘baby cells’! Symbiotica! Think about them sweet apples. Then reports women with daughters live longest.
New Protein ‘Receptors’. Large ‘family’ of evolutionary related receptor proteins (named ‘GPCR’) members targeted by 35% of approved drugs. Opioids, anti-histamines, beta-blockers, cannabinoid drugs, bronchodilators and loads more. During early decades of pharmacology research, number of GPCRs ‘settled’. ‘Sure that’s plenty enough’. New technology arrived by 1988-1990 along came ability to ‘explore’ genome, initially using information gleaned from few purified proteins (that challenging ‘heroic’ procedure)! Polymerase Chain Reaction (PCR) made possible go genome fishing, in what turned out to be ‘Haystack Net’ bulging with treasure trove haul of novel receptors. Previously hidden undiscovered most never predicted. Worldwide researchers left flabbergasted. GPCR ‘Family A’, revealing over 100 unknown receptors during prolific nineties decade, many no one ever heard neither sight nor sound. Recognized primarily by sequence similarities to purified ‘Adrenergic’ receptor, serving as family ‘Rosetta Stone’, brilliant scientists with heavy lifting effort purified this protein from tissue. Such harvest of new receptors initially mostly called ‘orphan’. Each receptor needs separate ‘activator’ when that’s unknown receptor declared ‘orphan’. Given track record of GPCR’s, new family members for sure eventually having benefit for multiple medical treatments, occurring now with ongoing Trials. Fingers crossed! Promise each will be targeted yielding ‘first in class therapeutics’, many targeting unmet needs. Promise for multitude of medically useful drugs for new targets. New candidates finally getting attention deserved, about time.
Overall discovery opportunity presented only once!
Ever.
For this Human Race
Good times ahead!.
Some new candidates graduated no longer lonely orphans. One leading that charge Apelin (aka APJ) receptor gene discovered (1993), now with promising leads benefits for heart disease. This busy receptor expressed in many organs. No doubt each bursting to contribute, created that way being helpful.
Protein Twins. Some genes have ‘twins’. D1 dopamine receptor gene revealed in 1990, six months later surprise with finding D5 dopamine receptor. D1 and D5 share similar pharmacology, over all 60% sequence identity, having some parts much higher. No previous clues concerning existence of D5. Following D2 dopamine receptor gene revealed in 1988 two related genes D3 and D4 since discovered! Serotonin now with 14 human receptor genes, many found by ‘cloning’! Wild times.
Pseudogenes. Such ‘genes’ contain tiny ‘errors’ ensure incapable of making functional proteins. Example our genome contains two D5 ‘pseudogenes’. Amino acid sequence for such genes share 90% identity to functional D5. Do they have a role to play or made redundant? None of us know so far. Likely sent to ‘Coventry’ sit waiting their turn-about, semi-retired. They had one job to do, now unoccupied, with no function. Thanks for your service pal. That’s life working, knows best.
Risk taking. Okay this is fascinating, D4 dopamine receptor gene uniquely contains ‘variable sequence region’, 48 nucleotide stretch, humans having from 2 to 11 repeats. Four repeats most common. Seven repeats associated with ‘Risk taking life style’! Not me having vertigo, experienced up the Pillar and Cliffs of Mohair. Shout out to Apollo Hero’s. Took us all up the notches.
Alzheimer’s Disease.
Genetic and environment factors increase risk of Alzheimer’s, still having no effective treatment. Not from want of trying. Some claim Alzheimer’s is an infection. Bright spot Lithium compounds may slow decline, reports they reverse ‘aging Brain and Alzheimer’s in mice’. Hope and pray.
Testicles why? Scrotum testicles produce sperm, high testosterone required an outside bag. Also hanging is cooler, early refrigeration. Got that right design! Sperm per ejaculation may we ponder? From 40 to 300 million, while hundreds ‘arrive’ on time. Only one winner, that’s each of us! Even for our down-trodden they once had Life’s Victorious moment. 1500 sperm cells made per second, 100 to 200 million per day, life time of trillions. Nature really really needs make sure! Testes sperm from puberty continues non-stop. Older men produce same numbers. Need look after family jewels, how otherwise? Once kicked by school yard bully, never forgotten! Good move Darwin, ‘inventing’ evolution. Works a treat with billions of us.
Down Syndrome. Named after John Langdon Down (1866). 95% cases caused by extra copy of Chromosome 21. Not inherited, error in womb with cell division. Also when not all cells have that extra chromosome 21, results with milder symptoms.
Human Gene editing. Some editing of human embryos restricted, while consequence still not understood. Editing human genome that could be inherited deemed illegal. In China two twin human fetuses were gene edited targeted gene CCR5, a variation known to HIV infection. Reportedly Scientist involved criticized for this. Scientists now examining long lived tortoise DNA (aged 190 years), search for regions to transplant in human! Likely will have slow progress.
Sex-determining region Y protein ‘SRY’. ‘Y’ chromosome contains unheralded SRY gene, that protein master switch for male development! Fully appreciated by me. Using ‘gene editing’ SRY gene knocked out in male pigs, babies adorned with female genitalia. Yikes!
‘Oh what tangled webs we weave,
when first practice interfering.
Careful! Out there.
‘SRY’ once male sex check in Olympics, now abandoned. SRY screening used in women’s events.
Blue Eyes. ~10% population with blue eyes, highest concentrations in northern Europe, including Ireland. Blue‑eyed people share an ancestor from 6,000–10,000 years, mutation in HERC2 gene, reduces melanin in the Iris, causing ‘light scattering that appears blue’. Survives from ‘Sexual selection’. Other words, looks so good!
One Amino Acid Error cause disease. Sickle cell anemia error in beta globin gene, Cystic Fibrosis in CFTR gene, Tay Sachs in Hex A, Sandhoff in Hex B, Thalassemia in beta globin. Does not take much to disrupt pristine designed protein sequence. With many more.
Chronic Obstructive Pulmonary disease (COPD). 5% of people with COPD have alpha-1 antitrypsin deficiency, protein protects lung tissue. Many alpha-1 antitrypsin gene variants producing no protein or misfolded protein. Other variants low level expressed in blood cells. Genetically disposed to lose lung function from low protein levels. Smokers beware!
Obesity. WHO records worldwide 940 million adults as obese. One in eight. From twin studies genetic component proven. Obesity risk found with ‘Mass and obesity-associated ‘FTO’ gene’, having protein variants associated with obesity, such individuals consumed more. People carrying FTO ‘European variant’ weighing ~2.6 lb more, having two gene copies weighed ~6.6 lb plus.
‘Guardian of genome’. Tp53 gene codes for p53 protein, tumor suppressor crucial to prevent cancers. Because of role ‘conserving stability’. ‘Li Fraumen’ rare disease caused by mutation in Tp53.
Gay Gene. DNA difference? One gene SLITRK6 role in developing brain, includes hypothalamus hormones control sex drive. Might be involved in development of male homosexuality. Also differences in TSHR gene, associated with ‘sexual orientation’ linked to thyroid. Other reports state there is no one single gene.
Gene therapy. Therapy to replace mutated gene with good gene. Use virus to carry gene into cells and inserted into genome. Since 2017, 14 such therapies approved.