Head coach Eddie Jones has named his team for a game which marks the 150-year anniversary of this fixture, with the first-ever international rugby match played between the two nations at Raeburn Place, Edinburgh in 1871.
Genge starts at loosehead prop for England in the Calcutta Cup match at Twickenham Stadium (4.45pm kick-off), with Youngs earning his 105th cap at scrum-half.
Owen Farrell starts at fly-half and captains England and Beno Obano could make his debut from the bench.
Jones said: “We’re really looking forward to getting the Guinness Six Nations back underway. It’s even more special to be taking part in a 150th anniversary game, it will be a good occasion.
“We’ve had a really good week of training, it’s been very competitive but I’ve gone with what I feel is the strongest 23 for this week.
“The Six Nations is a short tournament, it’s a real sprint, so we’ll need to be on the front foot straight away. We know Scotland will be raring to go – but so will we.”
England versus Scotland is live on ITV1 and BBC Radio 5 Live.
15 Elliot Daly (Saracens, 47 caps)
14 Anthony Watson (Bath Rugby, 46 caps)
13 Henry Slade (Exeter Chiefs, 34 caps)
12 Ollie Lawrence (Worcester Warriors, 3 caps)
11 Jonny May (Gloucester Rugby, 61 caps)
10 Owen Farrell (C) (Saracens, 88 caps)
9 Ben Youngs (Leicester Tigers, 104 caps)
1 Ellis Genge (Leicester Tigers, 23 caps)
2 Jamie George (Saracens, 54 caps)
3 Will Stuart (Bath Rugby, 8 caps)
4 Maro Itoje (Saracens, 43 caps)
5 Jonny Hill (Exeter Chiefs, 4 caps)
6 Mark Wilson (Newcastle Falcons, 19 caps)
7 Tom Curry (Sale Sharks, 28 caps)
8 Billy Vunipola (Saracens, 56 caps)
16 Luke Cowan-Dickie (Exeter Chiefs, 26 caps)
17 Beno Obano (Bath Rugby, uncapped)
18 Harry Williams (Exeter Chiefs, 18 caps)
19 Courtney Lawes (Northampton Saints, 85 caps)
20 Ben Earl (Bristol Bears, 8 caps)
21 Dan Robson (Wasps, 7 caps)
22 George Ford (Leicester Tigers, 72 caps)
23 Max Malins (Bristol Bears, 3 caps)