My Dopamine Receptor D4 (DRD4 ) 5 Prime Untranslated Region Promoter Variant/Novelty Seeking Trait In Connected to my Ashkenazi Jewish Ancestry and Evolution

This is a blog post about my Dopamine Receptor D4 5 Prime Untranslated Region Promoter Variant and Novelty Seeking Trait in connection to my Ashkenazi Jewish ancestry and Evolution.

I have been interested in the Dopamine Receptor D-4 (DRD4)  gene for almost two decades because of its connection to novelty seeking and Attention Deficit Hyperactivity Disorder (ADHD). Approximately 2.6% adults worldwide have persistent ADHD from childhood. Approximately 6.8% adults worldwide have symptomatic ADHD. I am a neurodivergent with Dyslexia, Dyspraxia, ADHD. I also have Ataxia which is a rare neurological condition.

 Almost two decades ago, I  got Thom Hartmann's book, The Edison Gene. It is based on the research studies of DRD4 7 Repeat allele which is present in 20% of the human population.  DRD4 7R allele has high frequency in the Americas but low frequency in Asia. It has been strongly linked to both ADHD (Attention Deficit Hyperactivity Disorder) and a behavior trait called "novelty seeking" which often underlies addiction. Scientists suggest that DRD4 7R occurred recently in human evolution between 10,000 and 40,000 years ago which was the period that anthropologists concur that humans were developing the first signs of complex societies involving agriculture, rudimentary governments, and the creation of cities for the first time. Humans were also rapidly expanding and exploring the planet. The DRD4 7R is shown to be an unusual, spontaneous mutation which became an advantage for humans, and so it became increasingly prevalent.

page 4 - 5 THE EDISON GENE ADHD And The Gift Of The Hunter Child by Thom Hartmann 

What exactly defines those bearing this genetic makeup? 

Edison-gene children and adults are by nature 

Enthusiastic

Disorganized

Non-linear in their thinking (they leap to new conclusions or observations)

Innovative

Easily distracted (or,to put it differently, easily attracted to new stimuli)

Capable of extraordinary hyperfous

Understanding of what it means to be an "outsider"

Determined

Eccentric

Easily Bored

Impulsive

Entrepreneurial

Energetic 

All of these qualities lead them to be natural: 

Explorers

Inventors

Discoverers

Leaders

https://www.goodreads.com/book/show/548387.The_Edison_Gene

Thom Hartmann points out that those carrying the DRD4 7 R often find themselves in environments where they're coerced, threatened,  or shoehorned into a classroom or job that doesn't fit. He said when Edison-gene children can be have great emotional and spiritual wounding when they are aren't recognized for their gifts but instead are told that they're disordered, broken, or failures. He points out that the wounding can bring all sorts of problems for children, for the adults they grow into, and for our society.  He and many scientists, educations, physicians, and therapists believe that when these unique children don't succeed in public schools, it's often because of a disconnect between them---their brains are wired to make them brilliant inventors and entrepreneurs--and our schools, which are set up for children whose brains are wired to make them good workers in the structured environments of a factory of office cubicle. 

https://www.nature.com/articles/s41398-021-01473-w 

https://link.springer.com/article/10.1007/s11682-021-00521-9

https://www.psychologytoday.com/us/blog/blame-the-amygdala/201909/the-curious-personality-the-drd4-7r-allele

https://www.psychologytoday.com/us/blog/the-gift-adhd/201604/adhd-and-the-rock-star-gene

Youtube Videos about DRD4

https://www.youtube.com/watch?v=mK3iiN9iUBU&t=231s

https://www.youtube.com/watch?v=QhhnKujYNw8

https://www.youtube.com/watch?v=U7n8ANrYEVs

https://www.youtube.com/watch?v=R9AOBLyxwEA

https://www.youtube.com/watch?v=sDRcVOl9res

My blog post about DRD4 and its connection to ADHD, Dyslexia, and Highly Sensitive Personality trait

https://neurodivergence.blogspot.com/2024/01/the-drd4-dopamine-receptor-d4-gene.html

DRD4 gene's position is 637,269 - 640,706 on Chromosome 11 which has a spans of over 135,000,000 base pairs

https://en.wikipedia.org/wiki/Chromosome_11

DRD4 is located near the beginning of Chromosome 11.

Over a decade ago, I got tested for the DRD4 7 Repeat allele through FamilyTreeDNA. I was told that I didn't have it.  I was a bit disappointed because I strongly felt that I had it. I can strongly relate to the DRD4 traits which I see in my mother and run strongly in my maternal grandfather's side of the family. From what my mother and paternal Aunt Carrie told me, my father had them too. After doing testing through the DNA company Sequencing around a year and half ago,  I have a variant that is noted as being Possible Risk for Hereditary Attention Deficit Hyperactivity Disorder.  It is located Chromosome 11, position 637294 with the reference allele being C and the alternate and risk allele being T.   My data shows C/T,  and so I have one copy of the risk allele. My mother has the variant. Her data for the same Single Nucleotide Polymorphism (SNP) shows as being C/T too.  Therefore, I inherited the variant from her.

https://gnomad.broadinstitute.org/variant/11-637294-C-T?dataset=gnomad_r4

https://www.ncbi.nlm.nih.gov/clinvar/RCV003239302/   

 According to Genome Aggregation Database (genomAD),  It is a 5 Prime Untranslated Region (5'UTR) Variant. It has an allele frequency of  5.169%.  It is highest in the Amish with a frequency of 9.051%, but it's a bottleneck population. The non-bottleneck population with the highest frequency is South Asians with a frequency of 7.873%.  It is lowest in East Asians with a frequency of 0.0193%. 

https://gnomad.broadinstitute.org/variant/11-637294-C-T?dataset=gnomad_r4 

 According to Ensembl's Variant Effect Predictor, it involves the Promoter.  Untranslated Regions and Promoters are critical regulatory features in genes.

In molecular genetics, an untranslated region (or UTR) refers to either of two sections, one on each side of a coding sequence on a strand of mRNA. If it is found on the 5' side, it is called the 5' UTR (or leader sequence), or if it is found on the 3' side, it is called the 3' UTR (or trailer sequence). mRNA is RNA that carries information from DNA to the ribosome, the site of protein synthesis (translation) within a cell. The mRNA is initially transcribed from the corresponding DNA sequence and then translated into protein. However, several regions of the mRNA are usually not translated into protein, including the 5' and 3' UTRs.

Although they are called untranslated regions, and do not form the protein-coding region of the gene, uORFs located within the 5' UTR can be translated into peptides.^[1]

The 5' UTR is upstream from the coding sequence. Within the 5' UTR is a sequence that is recognized by the ribosome which allows the ribosome to bind and initiate translation. The mechanism of translation initiation differs in prokaryotes and eukaryotes. The 3' UTR is found immediately following the translation stop codon. The 3' UTR plays a critical role in translation termination as well as post-transcriptional modification.^[2]

These often long sequences were once thought to be useless or junk mRNA that has simply accumulated over evolutionary time. However, it is now known that the untranslated region of mRNA is involved in many regulatory aspects of gene expression in eukaryotic organisms. The importance of these non-coding regions is supported by evolutionary reasoning, as natural selection would have otherwise eliminated this unusable RNA.

It is important to distinguish the 5' and 3' UTRs from other non-protein-coding RNA. Within the coding sequence of pre-mRNA, there can be found sections of RNA that will not be included in the protein product. These sections of RNA are called introns. The RNA that results from RNA splicing is a sequence of exons. The reason why introns are not considered untranslated regions is that the introns are spliced out in the process of RNA splicing. The introns are not included in the mature mRNA molecule that will undergo translation and are thus considered non-protein-coding RNA.

https://en.wikipedia.org/wiki/Untranslated_region

Ensembl data

Regions that are predicted to regulate gene expression are called Regulatory features in Ensembl. The different types of regulatory features annotated include:

Promoters (regions at the 5' end of genes where transcription factors and RNA polymerase bind to initiate transcription)

Promoter flanking regions (transcription factor binding regions that flank the above)

Enhancers (regions that bind transcription factors and interact with promoters to stimulate transcription of distant genes)

CTCF binding sites (regions that bind CTCF, the insulator protein that demarcates open and closed chromatin)

Transcription factor binding sites (sites which bind transcription factors, for which no other role can be determined as yet)

Open chromatin regions (regions of spaced out histones, making them accessible to protein interactions)

https://grch37.ensembl.org/info/genome/funcgen/regulatory_features.html

https://gnomad.broadinstitute.org/variant/11-637294-C-T?dataset=gnomad_r4 

My 23andme Ancestry Composition shows that most of the ancestry on Chromosome 11 that I inherited from my mother is Ashkenazi Jewish.  The Ashkenazi Jewish looks to be a segment that spans 3/4 of my maternal Chromosome beginning at position 1. Therefore the DRD4 gene is located on the shared Ashkenazi Jewish Chromosome 11 segment. My maternal grandmother's mother Ruth Rosenthal was a first generation Ashkenazi Jewish American with father Max Rosenthal born in Romania and Rachel 'Irene' Hosias born in Courland in the area in the Russian Empire that became Latvia.  23andme has me as being 9.3% Ashkenazi Jewish and my mother as 22.7% Ashkenazi Jewish. The DRD4 gene that my mother passed down to me was inherited from her late mother Beverly Floy Walker who inherited from her mother Ruth. The DRD4 gene is located on our shared Ashkenazi Jewish Chromosome 11 segment. 

Therefore, some of my novelty seeking trait comes from myAshkenazi Jewish ancestors. 

According to genomAD, the allele frequency of the DRD4 5'UTR variant in the Ashkenazi Jewish population is estimated to be 7.914% which is greater than the variant's world total population frequency of 5.169%.  Ashkenazi is a bottleneck population like the Amish though. 

I have other DRD4 variants.  I have an intronic variant 11-637622-C-T that is 328 base pairs downstream of my 5'UTR Promoter variant with an allele frequency of 5.871%. The 11-637622-C-T's frequency is highest in East Asians with a frequency of 14.62%. It is lowest in Africans/African Americans with a frequency of 2.017%.  Data is unavailable for my mother, and so I don't know about the inheritance.

https://gnomad.broadinstitute.org/variant/11-637622-C-T?dataset=gnomad_r4

https://www.ncbi.nlm.nih.gov/snp/rs752306#publications 

 I have an upstream variant in a Transcription Factor binding site 11-636929-C-T that is 365 base pairs upstream of my 5'UTR Promoter variant with an allele frequency of 3.415%. The 11-636929-C-T's frequency is highest in East Asians with a frequency of 16.81%. It is lowest in Africans/African Americans with a frequency of  0.8413%.   Data is unavailable for my mother, and so I don't know about the inheritance.

https://gnomad.broadinstitute.org/variant/11-636929-C-T?dataset=gnomad_r4

https://www.ncbi.nlm.nih.gov/snp/rs916455#publications

https://www.sciencedirect.com/science/article/abs/pii/S0165178112004489?via%3Dihub

I have an intronic variant in a CTCF binding site 11-637933-G-A that is 639 base pairs downstream of my 5'UTR Promoter variant with an allele frequency of 22.86%. The 11-637933-G-A's frequency is highest in Middle Easterners with a frequency of 34.01% closely followed by South Asians with a frequency of 33.35%. It is lowest in Africans/African Americans with a frequency of 11.47%.  

https://gnomad.broadinstitute.org/variant/11-637933-G-A?dataset=gnomad_r4

Data is unavailable for my mother, and my father is dead. Therefore, I don't know about the inheritance of my other DRD4 variants. 

Having any of these DRD4 variants doesn't necessarily mean that you have ADHD nor Dyslexia.  It could just be that you have abnormalities in the molecular functions and the biological processes of DRD4 that manifest into particular phenotypes. It could be that you're just a highly sensitive person that's a non-linear, visual, picture thinker and novelty seeker.  Having all four of the variants seems to point to being at high risk for ADHD and Dyslexia. I have variants in other genes that are thought to have connections to ADHD and Dyslexia, and some are uncommon and even rare. I also have rare variants that can explain my Ataxia and my overall neurodivergence. They include Missense variants which are medium impact coding region variants and high impact variants that include Stop Gained, Splice Acceptor, and Frameshift.  They also include 5'UTR upstream open reading frame (uORF) variants.

https://neurodivergence.blogspot.com/2024/01/my-neurological-makeup-includes-both.html

Some of DRD4's biological processes are involvement in behavioral fear response, involvement in fear response, and involvement in social behavior.  I know that I tend to easily feel  threatened and have strong reaction to perceived danger. I have a strong 'fight or flight' response.  If people have looks of anger and in my personal space, I feel very threatened and get very angry. I tend to overreact to emotional/social cues. 

I do wonder if my DRD4 variants factor into my being a very fast runner with quick reflexes when I was a young. I definitely believe that they're connected to my having a great reservoir of energy that keeps me from being tired from doing cardio even now in my early 50s, and that also factored in my being very fast runner when I was young because I was able to push myself very hard. My former track coach claimed in front of me and my track mates that I didn't get tired when running. He and other track coaches said that I run very hard.  I believe that my speed and hyperactivity were strongly connected.  I also believed that intensity was involved.  I had a tendency to ball up my fists when I run. The track coach often reminding to relax when I am running. I would tense up a lot. I ran track only briefly in sophomore year of high school because my grades were bad. 

I was diagnosed as having inattentive type ADHD in my 30s. I believe that I have a combined type. I didn't get diagnosed as having ADHD in childhood because my other neurodivergent conditions were masking it. There was much more concern about my speech, auditory processing, and coordination problems.  I got spanked a lot in my special education childhood years, and so that influenced me to have adequate behavior.  Instead of running around in the classroom, I was running around in my head. I saved my hyperactivity for outside the classroom except for fidgeting and talking a lot in classroom. Looking back, I now understand that I was always very nervous, highstrung, and anxious in classroom and work environments.  I now realize much of it was in connection to being overstimulated by the bright, flourescent lights that tend to be in the indoor environments and not just my feelings of intellectual inadequacy and information processing difficulties.

I  can strongly relate to what Thom Hartmann wrote in his book, The Edison Gene. Now I know that there is a genetic explanation for why I can.  It's not the DRD4 7R allele.  It's other variants in DRD4. They are involved in Evolution.