Transgenerational Latent Early-Life Associated Regulation Unites Environment and Genetics Across Generations

Abstract

The origin of idiopathic diseases is still poorly understood. The latent early-life associated regulation (LEARn) model unites environmental exposures and gene expression while providing a mechanistic underpinning for later-occurring disorders. We propose that this process can occur across generations via transgenerational LEARn (tLEARn). In tLEARn, each person is a ‘unit’ accumulating preclinical or subclinical ‘hits’ as in the original LEARn model. These changes can then be epigenomically passed along to offspring. Transgenerational accumulation of ‘hits’ determines a sporadic disease state. Few significant transgenerational hits would accompany conception or gestation of most people, but these may suffice to ‘prime’ someone to respond to later-life hits. Hits need not produce symptoms or microphenotypes to have a transgenerational effect. Testing tLEARn requires longitudinal approaches. A recently proposed longitudinal epigenome/envirome-wide association study would unite genetic sequence, epigenomic markers, environmental exposures, patient personal history taken at multiple time points and family history.

Keywords::

• aging
• childhood
• development
• epigenetics
• experiences
• insult
• intergenerational
• late life
• neurodegenerative
• nutrition
• post traumatic

Financial & competing interests disclosure

The work was supported by grants from the National Institute on Aging, NIH R01-AG051086 and R21-AG042804; and Indiana Clinical & Translational Sciences Institute (ICTSI) and Indiana Spinal Cord and Brain Injury Research Fund (ISCBIRF); P30 AG010133 Indiana Alzheimer Disease Research Center, and R21 sub-award from Purdue University to DK Lahiri. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

The work was supported by grants from the National Institute on Aging, NIH R01-AG051086 and R21-AG042804; and Indiana Clinical & Translational Sciences Institute (ICTSI) and Indiana Spinal Cord and Brain Injury Research Fund (ISCBIRF); P30 AG010133 Indiana Alzheimer Disease Research Center, and R21 sub-award from Purdue University to DK Lahiri. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.