Genetics and covid deaths

Neanderthal gene probably caused up to a million Covid deaths

LZTFL 1 gene

The major genetic risk factor for severe COVID-19 is inherited from Neanderthals

Clinical manifestations, asymptomatic to rapid progression to respiratory failure

Co-morbidities do not fully explain variability

Region (gene cluster) on chromosome 3

Only region that is significantly associated with severity

Odds ratio for requiring hospitalization of 1.6

Death, 2.0

Genome-wide association study

N = 3,199 hospitalized with COVID-19

Population controls, 897,488

The major genetic risk factor for severe symptoms

Risk is conferred by genomic segment, 50 kilobases

Inherited from Neanderthals

Haplotype

Group of alleles (one version of a gene) in an organism that are inherited together from a single parent.

Sequence strongly associated with each other in the population

Haplotype carried by

50% of people in south Asia, at least one copy

16% of people in Europe

9% of admixed American

Bangladesh

63% heterozygous

13% homozygous

Bangladeshi origins, living in UK

Hazard ratio of death, 2.0

Almost absent in east Asia

Neanderthals or Denisovans?

Present in a homozygous form in the genome of Vindija Neanderthal,

50,000-year-old Neanderthal from Croatia

Founder of the clade

Neanderthals and modern humans split 550,000 years ago

Dr James Davies University of Oxford

We used the technique and it identified a virtually understudied gene called LZTFL1,

and at the time that this had not been linked to infection at all.

It’s a single letter difference out of three billion.

This tiny section of DNA doubles your risk of dying from Covid.

It's position 45,818,159 on chromosome three,

and it's a single change.

If you've got a G at that site, it's low risk.

And if you have an A at that site it is high risk

adenine (A)

cytosine (C)

guanine (G)

thymine (T)

Gene changes cell reaction to binding of SARS-CoV-2 virus onto the ACE2 receptor

Conformational changes

In most people, this leads to the cell then changing shape

Conformational changes reduces further binding

High risk variant, less or delayed conformational change

Deaths globally, is in the hundreds of thousands to a million

Dr Davies and Dr Simon Underdown

The Neanderthal gene first infiltrated humans 60,000 years ago

One event, one child

Neanderthal Introgression,

Gene jumped into the Homo sapien lineage

The reason that we know that is that it's inherited as this block with 28 single letter changes,

and you can track that all the way back and it has to be a single event.

It's just so unlikely that you get all 28 changes at the same time and in the same block